Charles E. Rupprecht, David R. Shlim

Infectious Agent

Rabies is an acute, progressive, fatal encephalomyelitis caused by neurotropic viruses in the family Rhabdoviridae, genus Lyssavirus. Regardless of the viral variant found throughout the world, all lyssaviruses cause rabies.

Mode of Transmission

• The disease is almost always transmitted by an animal bite that inoculates virus into wounds.
• Very rarely, rabies virus has been transmitted by exposures other than bites that introduce the virus into open wounds or mucous membranes.
• All mammals are believed to be susceptible, but reservoirs are carnivores and bats.
• Although dogs are the main reservoir in developing countries, the epidemiology of the disease differs sufficiently enough from one region or country to another to warrant the medical evaluation of all mammal bites.
• Bat bites anywhere in the world are a cause of concern and an indication for prophylaxis.

Pathophysiology of Rabies

• Rabies virus is present in the saliva of the biting mammal.
• The virus that is inoculated into the wound does not enter the bloodstream. The virus must be taken up at a nerve synapse to travel to the brain, where it causes a fatal encephalitis. The virus may enter a nerve rapidly, or it may remain at the bite site for an extended period before gaining access to the nervous system. The density of nerve endings in the region of the bite increases the risk of developing rabies encephalitis more rapidly. The hands and face, because of the density of nerve endings, are considered higher-risk exposures.
• Prevention of rabies encephalitis is dependent upon preventing the virus from entering a peripheral nerve. This can be accomplished by wound cleansing and disinfection, instillation of rabies virus neutralizing antibodies into the wound, and stimulating an active immune response with a series of rabies vaccine injections.

Occurrence

• Rabies is found on all continents except Antarctica.
• In certain areas of the world, canine rabies remains highly endemic, including but not limited to parts of Africa, Asia, and Central and South America. Table 2-16 lists countries that have reported no cases of rabies during the most recent period for which information is available (formerly referred to as “rabies-free” countries).
• Additional information about the global occurrence of rabies can be obtained from:
  • The World Health Organization (www.who.int/rabies/rabnet/en/)
  • The Pan American Health Organization (www.paho.org/english/ad/dpc/vp/rabia.htm)
  • The Rabies Bulletin—Europe (www.rbe.fli.bund.de)
  • The World Organization for Animal Health (www.oie.int/eng/en_index.htm)
  • Other sources are local health authorities of the country, the embassy, or the local consulate’s office in the United States.

Lists are provided only as a guide, because up-to-date information may not be available, surveillance standards vary, and reporting status can change suddenly as a result of disease re-introduction or emergence.

Risk for Travelers

• The actual rate of possible rabies exposure in tourists has not been calculated with accuracy. However, studies have found a range of roughly 16 to 200 per 100,000 based on differing criteria.
• Travelers to rabies-endemic countries should be warned about the risk of acquiring rabies and educated in animal bite prevention strategies.
• Street dogs represent the most frequent risk for bite exposure to travelers, followed by monkeys, especially those that live near temples in parts of Asia. Travelers should be instructed not to approach these animals and to be aware of their surroundings so that they do not surprise a dog in a confined space. If a dog is charging at a person, stooping to pick up a rock (or pretending to pick up a rock) can often make the dog turn and run away.
• Monkeys are attracted to food and may jump on travelers’ backs if there is food in their backpacks.
• Children are considered to be at high risk from rabies virus exposures because their small stature makes extensive bites more likely, they are attracted to animals, and there is the remote possibility that they may not report a possible exposure.
• Casual exposure to cave air is not a concern, but cavers should be warned not to handle bats. Noncavers can occasionally encounter a bat. Many bats have tiny teeth, and not all wounds may be appreciated compared with the lesions caused by carnivores. Any suspected or documented bite or scratch from a bat should be grounds for seeking postexposure rabies immunoprophylaxis.

Clinical Presentation

• After infection, the incubation period is highly variable, but lasts approximately 1–3 months.
• The disease progresses from a nonspecific prodromal phase to paresis or paralysis; spasms of swallowing muscles can be stimulated by the sight, sound, or perception of water (hydrophobia); and delirium and convulsions can develop, followed rapidly by coma and death.

Diagnosis

• Definitive diagnosis can be made by demonstrating the presence of the rabies virus in corneal impressions or nuchal biopsy, either through staining or polymerase chain reaction.
• A serologic response to rabies virus can also prove the diagnosis.

Treatment

No treatment is effective after the development of clinical signs, but the extremely rare case of recovery after extensive medical intervention offers hope that future experimental therapeutics may be developed.

Preventive Measures for Travelers

• Prevention of possible exposures to rabies virus is best accomplished by avoiding bites from mammals (mainly dogs, monkeys, bats, and cats in some countries).
• Although licks from animals to fresh wounds or mucus membranes of humans are a theoretical risk of acquiring rabies and postexposure prophylaxis should be considered, there are no examples of rabies in travelers who were exposed in this way.
• Travelers should be counseled to avoid approaching stray animals, to be aware of their surroundings so that they do not accidentally surprise a stray dog, to avoid contact with bats, and not to carry or eat food while walking among monkeys.
• In addition to avoiding bite exposures, two strategies are available to travelers for the prevention of rabies: vaccination and management of a possible rabies exposure (see sections below for more specific details).
• For certain international travelers, pre-exposure rabies vaccine may be recommended, based on the local incidence of rabies in the country to be visited, the availability of appropriate anti-rabies biologicals, and the intended activity and duration of stay of the traveler.
  • A decision to receive pre-exposure rabies immunization may also be based on the likelihood of repeat travel to at-risk destinations over time or taking up residence in a high-risk destination.
  • Pre-exposure vaccination may be recommended for veterinarians, animal handlers, field biologists, cavers, missionaries, and certain laboratory workers. Table 2-17 provides criteria for pre-exposure vaccination.
• Immediate and adequate medical care after an animal bite is critical to preventing rabies (see Management of a Possible Rabies Exposure below). Regardless of whether or not pre-exposure vaccine is administered, travelers going to areas with a high risk for rabies should be especially encouraged to purchase medical evacuation insurance (see the Travel Insurance and Evacuation Insurance section later in this chapter).

Vaccine

Pre-Exposure Vaccination

• In the United States, pre-exposure vaccination consists of a series of three injections with human diploid cell rabies vaccine (HDCV) or purified chick embryo cell (PCEC) vaccine.
• The schedule for this series in given in Table 2-18.
• In the event of a possible rabies exposure in someone who has received pre-exposure rabies immunization, rabies immune globulin (RIG) is not given, and two boosters of an acceptable rabies vaccine are given on days 0 and 3. The booster doses need to be modern cell culture vaccines, but they do not need to be the same brand as the vaccine given in the pre-exposure immunization series.
• Pre-exposure immunization does not eliminate the need for additional medical attention after a rabies exposure, but it greatly simplifies postexposure prophylaxis.
• Pre-exposure vaccination may also provide some degree of protection when there is an unapparent or unrecognized exposure to rabies virus and when postexposure prophylaxis might be delayed.
• Travelers should receive all three pre-exposure immunizations before travel. If three doses of rabies vaccine cannot be completed prior to travel, the traveler should not start the series, as it would be problematic to plan postexposure prophylaxis after a partial immunization series.

Beginning in June of 2007 and lasting until the end of March 2009, the supply of rabies vaccine in the United States was limited. As a result, during this time, pre-exposure rabies vaccination was not available to international travelers, except under special circumstances. The supplies of rabies vaccine have been restored, and the pre-exposure vaccination recommendations listed above should be followed. (Updated August 24, 2009)

Postexposure Vaccination

• If pre-exposure rabies immunization is not given, the traveler will need to obtain full postexposure rabies prophylaxis in the event of a possible rabies virus exposure. This consists of injections of RIG (20 IU/kg) and a series of five injections of rabies vaccine over a 1-month period.
• Because RIG or rabies vaccine may not be available in the destination country, travelers should have a strategy in place before travel as to how to respond to a possible exposure. This strategy may require the traveler to fly to a different country to obtain the appropriate prophylaxis.
• Different postexposure vaccine schedules, alternative routes of administration, and other rabies vaccines besides HDCV and PCEC may be used abroad. Although not approved for sale in the United States, purified vero cell rabies vaccine and purified chick embryo cell vaccine (manufactured abroad) are acceptable alternatives if available in a destination country.
• Historically, rabies vaccine was once manufactured from viruses grown in animal brains, and some of these vaccines are still in use in developing countries. The brain-derived vaccines can be identified if the traveler is offered a large injection (5 mL) daily for 14–21 days. The traveler should not accept these vaccines, but rather should travel to a country where acceptable vaccines and immune globulin are available.

Management of a Possible Rabies Exposure

• Travelers should be advised that any animal bite or scratch should receive prompt local first aid by thorough cleansing of the wound with copious amounts of soap and water and povidone iodine, if available. This local care will substantially reduce the risk for rabies.
• Wounds that might require suturing should have the suturing delayed for a few days. If suturing is necessary for control of bleeding or for functional or cosmetic reasons, RIG should be administered into the wound before closing the wound. The use of local anesthetic is not contraindicated in wound management.
• Human rabies immune globulin (HRIG) is manufactured by plasmapheresis of hyperimmunized volunteers. The manufactured quantity of HRIG falls short of worldwide requirements, and the substance is not available in many developing countries. Equine rabies immune globulin (ERIG) or purified fractions of ERIG have been used effectively in some developing countries where HRIG might not be available. If necessary, such heterologous products are preferable to no RIG administration in human rabies postexposure prophylaxis.
• The incidence of adverse reactions after the use of these products has been low (0.8%–6.0%), and most of those reactions were minor. However, such products are neither evaluated by U.S. standards nor regulated by the FDA, and their use cannot be unequivocally recommended at this time. In addition, unpurified antirabies serum of equine origin might still be used in some countries where neither HRIG nor ERIG is available. The use of this antirabies serum is associated with higher rates of serious adverse reactions, including anaphylaxis.
• After wound cleansing, as much of the calculated amount of RIG (see Table 2-19) as is anatomically feasible is infiltrated around the wound. The dose injected around the wound may be as small as 0.5 mL if the wound is small or on a finger. If the wounds are extensive, the calculated dose of RIG must not be exceeded. If the calculated dose is inadequate to inject all the wounds, the RIG should be diluted with normal saline to extend the number of wounds that can be injected. This is a particular issue in children, whose body weight may be small in relation to the size and number of wounds.
• The remainder of the RIG dose, if any, should be injected intramuscularly. Care should be taken to guarantee that this remaining amount of RIG is deposited in a muscle and not injected subcutaneously, which may decrease its effectiveness. The remaining RIG can be given in the deltoid muscle, on the opposite side of the initial vaccine dose. The anterior thigh is also an alternative site.
• RIG should not be given more than 7 days after the start of the postexposure vaccine series. This 7-day period does not relate to the time of the bite exposure itself.
• Postexposure prophylaxis, including RIG, should be initiated after a possible bite exposure even if there has been a considerable delay between the exposure and the traveler presenting for evaluation.
• Travelers who have completed a three-dose pre-exposure rabies immunization series or have received the full postexposure prophylaxis are considered pre-immunized and do not require routine boosters, except after a possible rabies exposure.
• Periodic serum testing for rabies antibody is not necessary in routine international travelers.

Vaccine Safety and Adverse Reactions

• Travelers should be advised that they may experience local reactions after vaccination, such as pain, erythema, swelling, or itching at the injection site, or mild systemic reactions, such as headache, nausea, abdominal pain, muscle aches, and dizziness.
• Approximately 6% of persons receiving booster vaccinations with HDCV may experience an immune complex-like reaction characterized by urticaria, pruritus, and malaise. The likelihood of these reactions is less with PCECV.
• Once initiated, rabies postexposure prophylaxis should not be interrupted or discontinued because of local or mild systemic reactions to rabies vaccine.

Precautions and Contraindications

• Pregnancy is not a contraindication to postexposure prophylaxis.
• In infants and children, the dose of HDCV or PCEC for pre-exposure or postexposure prophylaxis is the same as that recommended for adults. The dose of RIG for postexposure prophylaxis is based on body weight (Table 2-19).

References

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2. Strauss R, Granz A, Wassermann-Neuhold M, et al. A human case of travel-related rabies in Austria, September 2004. Euro Surveill. 2005;10(11):225–6.
3. Smith A, Petrovic M, Solomon T, et al. Death from rabies in a UK traveller returning from India. Euro Surveill. 2005;10(30):2761.
4. Jackson AC, Warrell MJ, Rupprecht CE, et al. Management of rabies in humans. Clin Infect Dis. 2003;36(1):60–3.
5. CDC. Human Rabies Prevention—United States, 2008: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2008;57(RR-03):1–28.
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