The risk of developing rabies following a bite or scratch by a rabid animal depends on whether the wound was a bite, scratch, or nonbite exposure; the number of bites; the depth of the bites; and the location of the wounds (Table 157-4).13
TABLE 157-4Risk of Rabies in the Absence of Postexposure Prophylaxis after Exposure to a Rabid Animal ||Download (.pdf) TABLE 157-4 Risk of Rabies in the Absence of Postexposure Prophylaxis after Exposure to a Rabid Animal
Multiple severe bites around the face: 80%–100%
Single bite: 15%–40%
Superficial bite(s) on an extremity: 5%
Contamination of a recent wound by saliva: ~0.1%
Contact with rabid saliva on a wound older than 24 hours: 0%
Transmission via fomites (e.g., tree branch): theoretical*
Indirect transmission (e.g., raccoon saliva on a dog): theoretical*
Risk assessment for postexposure prophylaxis includes determining the epidemiology of animal rabies in the area where the contact occurred; knowing the species of animal involved; understanding the type of exposure (e.g., bite versus nonbite); clarifying the circumstances of the exposure incident; and determining if the animal can be safely captured and tested for rabies (Table 157-5). The distinction between a "provoked" and "nonprovoked" attack should not be used for risk assessment. Most animal bites are "provoked" from the standpoint of the animal (i.e., interfering with the animal's food, offspring, feeding habits, etc.). In addition, about 15% of animals with rabies do not exhibit aggressive behavior but are apathetic ("dumb rabies"). The local health department can provide information about the epidemiology of animal rabies in the area. Evaluation for postexposure prophylaxis is indicated for persons bitten by, scratched by, or exposed to saliva from a wild or domestic animal that could be rabid (Figure 157-1).
TABLE 157-5Rabies Postexposure Risk Assessment and Recommendations (2012)14 ||Download (.pdf) TABLE 157-5 Rabies Postexposure Risk Assessment and Recommendations (2012)14
|Animal Type ||Evaluation and Disposition of Animal ||Postexposure Prophylaxis Recommendations |
|Dogs, cats, and ferrets || |
Healthy and available for 10 d of observations
Rabid or suspected rabid
Unknown (e.g., escaped)
Persons should not begin vaccination unless animal develops clinical signs of rabies.*
Consult public health officials.
|Skunks, raccoons, foxes, and most other carnivores; bats† ||Regard as rabid unless animal proven negative for rabies virus by laboratory tests‡ ||Consider immediate immunization. |
|Livestock, horses, rodents, rabbits and hares, and other mammals ||Consider individually ||Consult public health officials; bites of squirrels, hamsters, guinea pigs, gerbils, chipmunks, mice, rats, rabbits, hares, and other small rodents almost never require rabies postexposure prophylaxis. |
Clinical guidelines for administration of postexposure prophylaxis. (*) Consider postexposure prophylaxis for persons who were in the same room as a bat and who might be unaware that a bite or direct contact had occurred. (†) The small mammals listed here have never been reported to transmit rabies to humans in the United States, but theoretically, such animals could acquire and transmit rabies. Therefore, postexposure prophylaxis following a bite or scratch from one of these mammals would only be indicated if such an animal had signs typical of rabies or a positive laboratory test for rabies. Consult with local public health officials for reports of rabies in atypical animals. FAT = fluorescent antibody testing; HRIG = human rabies immune globulin.
Give postexposure prophylaxis as soon as possible after exposure to rabies-prone wildlife (Tables 157-5 and 157-6).
TABLE 157-6Summary of Risk of Acquiring Rabies in the United States ||Download (.pdf) TABLE 157-6 Summary of Risk of Acquiring Rabies in the United States
|Risk ||Exposures |
|Moderate to high || |
Bite by skunk, raccoon, fox, and other wild carnivores (unless animal tested negative for rabies)
Bite or direct contact with bat (unless animal tested negative for rabies)
Exposure by percutaneous injury, mucous membrane exposure, or inhalation to live rabies virus in a laboratory
Dog bite in a country with endemic rabies and inadequate immunization of dogs (or bite by feral dog)
|Very low to low || |
Bite by inadequately vaccinated cat or dog that has access to the outdoors (or feral cat or dog)
Contamination of open wound or abrasion (including scratches) with, or mucous membrane exposure to, saliva or other potentially infectious material (e.g., neural tissue) from a possibly rabid animal (skunk, raccoon, fox, and other wild carnivores, bat)
Awakening in a room with a bat present
|No risk identified || |
Contact of animal fluids (e.g., saliva, blood, neural tissue) with intact skin
Indirect contact with saliva from a wild animal (e.g., by cleaning a dog or cat that has had contact with a wild animal)
For the purpose of rabies postexposure prophylaxis, a bite exposure is defined as any penetration of the skin by the teeth of an animal.12 Bites to the face and hands carry the highest risk, but the site of the bite does not influence the decision to begin therapy.
A nonbite exposure is contamination of scratches, abrasions, open wounds, or mucous membranes with saliva or brain tissue from a rabid animal. For example, animal licks to nonintact skin have transmitted rabies. Nonbite exposures from animals very rarely cause rabies. If the material containing the virus is dry, the virus can be considered noninfectious. Petting a rabid animal or contact with blood, urine, or feces (e.g., guano) of a rabid animal does not constitute an exposure and is not an indication for prophylaxis.12
Exposures to Animals Previously Vaccinated for Rabies
A fully vaccinated dog or cat (i.e., two vaccinations) is unlikely to become infected with rabies. No documented vaccine failures have been reported in the United States among dogs or cats that received two vaccinations. Rare cases have been reported among animals that had received only a single dose of vaccine. In the United States, animals other than dogs, cats, and ferrets that can transmit rabies and are the source of an animal bite or scratch to a human should be euthanized and tested for rabies even if the animals have been vaccinated.
Any direct contact between a human and a bat should be evaluated for a rabies exposure. Seeing a bat does not constitute an exposure. Postexposure prophylaxis is not indicated if the person can be certain that a bite, scratch, or mucous membrane exposure did not occur or if the bat is available for testing and results are negative for the presence of rabies virus. All bats that might be a source of exposure, if available, should be sent to the public health department and tested for rabies, because approximately 94% of submitted bats in the United States have tested negative for rabies.8 The Advisory Committee on Immunization Practices recommends consideration of postexposure prophylaxis for persons who were in the same room as a bat and who were unaware if a bite or direct contact had occurred (e.g., a sleeping person awakens to find a bat in the room, or an adult witnesses a bat in a room with an unattended child, mentally disabled person, or intoxicated person).12,14 One article calculated the incidence of rabies following bedroom exposure with contact as 0.6 cases per billion person-years,8 whereas another article reported that the number needed to treat to prevent a single case of rabies in this context would be 314,000 to 2.7 million persons.15
Bites from Healthy-Appearing Animals
The Centers for Disease Control and Prevention recommends that a healthy dog, cat, or ferret that bites a person be confined and observed for 10 days.12,14 At the first sign of illness during confinement, such animals should be evaluated by a veterinarian and a report immediately made to the local health department. If signs suggestive of rabies develop, the animal should be euthanized and its head removed and shipped under refrigeration (not frozen) for examination of the brain by a qualified laboratory designated by the local or state health department.
Any stray or unwanted dog, cat, or ferret that bites a person may be euthanized immediately and the head submitted for rabies examination. Animals that might have exposed a person to rabies should be reported immediately to the local health department. An animal other than a dog, cat, or ferret that received prior vaccination may still require euthanasia and testing if the period of virus shedding is unknown for that species.
There are anecdotal reports of person-to-person transmission of rabies. Fluids from the upper and lower respiratory tracts of humans frequently test positive for rabies virus. Despite the lack of proven healthcare-associated transmission, about 30% of healthcare personnel who have had contact with a human diagnosed with rabies have received postexposure prophylaxis. Given the mechanism of disease transmission and concern among healthcare workers, contact isolation precautions should be used for patients with known or suspected rabies, and healthcare workers who care for such patients should wear either masks and eye protection or face shields.12 Healthcare personnel with nonintact skin or mucous membrane exposure to infective saliva from patients with rabies should receive postexposure prophylaxis.
Patients Concerned about Rabies
For unusual exposures, the state veterinarian or local public health agency can be contacted for more information. However, for patients who voice concern about rabies exposure even if the risk assessment is virtually nil (Table 157-6), vaccination can be offered, along with an explanation of the risks and benefits of vaccination. If the risk of rabies is virtually nil, we discourage the administration of HRIG.
First, assess wounds for the presence of a life-threatening condition, such as arterial laceration or pneumothorax.16 Provide proper wound care, including tetanus prophylaxis, wound cleansing with soap and water and (if available) a dilute solution of povidone-iodine (1 mL povidone-iodine in 9 mL of water or normal saline), antibiotics (if indicated) to prevent bacterial infection (see chapter 46, Puncture Wounds and Bites), and rabies prophylaxis as indicated.17
POSTEXPOSURE PROPHYLAXIS TREATMENT
In the United States, postexposure prophylaxis consists of a regimen of one dose of HRIG and four doses of rabies vaccine over a 14-day period, except for immunocompromised persons, who should receive a five-dose series of vaccine over a 28-day period (Table 157-7).14,17 The shift from a five-dose to a four-dose series of rabies vaccine occurred in 2010 and is based on rabies virus pathogenesis, experimental animal studies, clinical trials, epidemiologic surveillance, and economic analyses.17 No other aspects of postexposure prophylaxis were altered from the 2008 recommendations (e.g., use of HRIG, site of injection, etc.). HRIG and the first dose of rabies vaccine should be given as soon as possible after exposure, preferably within 24 hours. If HRIG was not administered when vaccination was begun, it can be administered up to 7 days after administration of the first dose of the vaccine.
TABLE 157-7Rabies Postexposure Prophylaxis Schedule—United States, 2010 ||Download (.pdf) TABLE 157-7 Rabies Postexposure Prophylaxis Schedule—United States, 2010
|Immunization Status ||Treatment ||Regimen* |
|Not previously immunized || |
Cleanse all wounds with soap and water; irrigate wounds with 9:1 diluted solution of povidone-iodine (if available).
Administer 20 IU/kg actual body weight. If anatomically feasible, infiltrate the full dose around the wound(s) and give any remaining volume IM at an anatomic site distant from vaccine administration; do not give HRIG in the same syringe as vaccine. HRIG may partially suppress active production of rabies virus antibody, so do not give more than the recommended dose.
HDCV or PCECV 1.0 mL (deltoid area†), one dose on days 0,‡ 3, 7, and 14.#
|Previously immunizedƒ || |
Cleanse all wounds with soap and water; irrigate wounds with 9:1 povidone-iodine solution.
HRIG should not be administered.
HDCV or PCECV 1.0 mL (deltoid area†), one dose on days 0‡ and 3.
Follow the Centers for Disease Control and Prevention recommendations for postexposure prophylaxis exactly (Table 157-7). Although no postexposure prophylaxis vaccine failures have been reported in the United States since the licensing of human diploid cell vaccine in 1980, 13 persons outside the United States have contracted rabies after postexposure prophylaxis with tissue culture–derived vaccine.2 Each of these cases involved deviation from the recommended protocol; wounds were not cleansed, passive immunization with HRIG was not provided, or rabies vaccine was injected into the gluteal rather than the deltoid area.
Rabies vaccines available in the United States include human diploid cell vaccine (produced in human diploid cells; Imovax®, Sanofi Pasteur, Lyon, France) and purified chick embryo cell culture vaccine (PCECV) (produced in chick embryo cells; RabAvert®, Novartis Vaccines, Emeryville, CA). The active antibody response requires approximately 7 to 10 days to develop, and detecTable rabies virus–neutralizing antibodies generally persist for several years. All currently used vaccines are produced in cell cultures and are significantly less toxic than older vaccines that were produced in neural tissue. Side effects of human diploid cell vaccine, including mild erythema, swelling, and pain at the injection site, have been reported in 10% to 90% of vaccine recipients. Systemic reactions, such as headache, nausea, abdominal pain, muscle aches, and dizziness, have been reported in 5% to 40% of recipients. Serum sickness–like reactions (type III hypersensitivity) have been noted in approximately 6% of persons receiving booster doses of human diploid cell vaccine and occur 2 to 21 days after administration of the booster dose. Such reactions have not been life threatening and have not been reported with purified chick embryo cell culture vaccine. Anaphylaxis and neurologic symptoms have only rarely been associated with the current rabies vaccines. Severe egg allergy is a contraindication to the use of purified chick embryo cell culture vaccine.
Rabies prophylaxis should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine.16 Usually such reactions can be successfully managed with anti-inflammatory and antipyretic agents. When a person with a history of serious hypersensitivity to rabies vaccine must be revaccinated, antihistamines may be given. Epinephrine should be readily available to counteract anaphylactic reactions, and the person should be observed carefully immediately after vaccination (as after any other injection given in a healthcare setting).
Human Rabies Immunoglobulin
HRIG is administered only once, at the beginning of antirabies prophylaxis, to provide immediate antibodies until the patient responds to rabies vaccine by producing antibodies. A passive antibody titer is evident in 24 hours. Failure to administer HRIG has led to rabies despite appropriate postexposure prophylaxis with human diploid cell vaccine. If HRIG was not given when vaccination was begun, it can be given through the seventh day after administration of the vaccine.17 Beyond the seventh day after vaccination is begun, HRIG is not indicated, because an antibody response is presumed to have occurred. The Centers for Disease Control and Prevention recommends that as much as possible of the full dose be infiltrated around the wound. HRIG should never be administered in the same syringe or into the same anatomic site as the vaccine. Even if the wound has to be sutured, it should be infiltrated locally with HRIG. This practice is safe and does not create an additional risk of infection. However, caution is needed when injecting into a tissue compartment, such as the finger pulp, because excessive HRIG can increase compartment pressure and lead to necrosis.18 Any remaining HRIG that cannot be administered into the local wound area should be injected intramuscularly at a site distant from vaccine administration. HRIG is prepared from human blood and screened for known viruses (e.g., human immunodeficiency virus, hepatitis). No cases of virus transmission from HRIG that is commercially available in the United States or Australia have been reported. HRIG should not be given to those with immunoglobulin A deficiencies and known antibodies of immunoglobulin A, because small amounts of immunoglobulin A may be present in HRIG and can cause a severe allergic reaction.
WORLD HEALTH ORGANIZATION POSTEXPOSURE PROPHYLAXIS GUIDELINES
In the United States, only regimens recommended by the Advisory Committee on Immunization Practices should be used. The World Health Organization has provided recommendations for rabies postexposure prophylaxis that also consider the cost and availability of vaccines and HRIG.19,20 Per the World Health Organization, the indication for postexposure prophylaxis depends on the contact with the suspected rabid animal:
Category I: touching or feeding animals, licks on intact skin (that is, no exposure)
Category II: nibbling of uncovered skin, minor scratches or abrasions without bleeding
Category III: single or multiple transdermal bites or scratches, contamination of mucous membrane with saliva from licks, licks on broken skin, exposure to bats
For category I exposures, no prophylaxis is required. For category II, immediate vaccination is recommended. For category III, immediate vaccination and administration of rabies immunoglobulin are recommended. Per the World Health Organization, factors that should be taken into consideration when deciding whether to initiate postexposure prophylaxis include the epidemiologic likelihood of the implicated animal being rabid, the category of exposure (i.e., I, II, or III), and the clinical features of the animal, as well as its availability for observation and laboratory testing. In most situations in developing countries, the vaccination status of the implicated animal alone should not be considered when deciding whether to give or withhold prophylaxis.
For IM administration, the World Health Organization recommends the following postexposure regimens. The postexposure vaccination schedule is based on injecting 1 mL or 0.5 mL (volume depends on the type of vaccine) into the deltoid muscle (or anterolateral thigh in children <2 years of age) of patients with category II and III exposures. The recommended regimen consists of either a 5-dose or a 4-dose schedule:
The five-dose schedule consists of one dose on each of days 0, 3, 7, 14, and 28.
The four-dose schedule consists of two doses on day 0 (one dose in each of the two deltoid or thigh sites) followed by one dose on each of days 7 and 21.
An alternative for healthy, fully immunocompetent, exposed persons who receive wound care plus high-quality rabies immunoglobulin plus World Health Organization–prequalified rabies vaccines is a postexposure regimen consisting of four doses administered intramuscularly on days 0, 3, 7, and 14.
For intradermal administration, the World Health Organization recommends the following postexposure regimen: The two-site regimen prescribes injection of 0.1 mL at two sites (deltoid and thigh) on days 0, 3, 7, and 28. This regimen may be used for people with category II and III exposures in countries where the intradermal route has been endorsed by national health authorities.
POSTEXPOSURE PROPHYLAXIS IN SPECIAL POPULATIONS
Persons with Prior Rabies Immunization
If exposed to rabies, persons previously vaccinated should receive two intramuscular doses (1 mL each) of vaccine, one immediately and one 3 days later.14,17 "Previously vaccinated" refers to persons who have received one of the recommended preexposure or postexposure prophylaxis regimens of human diploid cell vaccine or purified chick embryo cell culture vaccine, or those who have received another vaccine and had a documented accepTable rabies antibody titer. HRIG is unnecessary and should not be given in these cases, because an anamnestic antibody response will follow the administration of a booster regardless of the prebooster antibody titer.
Immunization of immunocompromised persons presents special challenges. First, vaccines may represent a danger to the immunocompromised individual. Second, the immune response to vaccination may be insufficient. Higher doses or additional immunizations may be required, and even with these modifications, the immune response may be suboptimal. The severely immunocompromised are those who have congenital immunodeficiency, human immunodeficiency virus infection, leukemia or lymphoma, aplastic anemia, or generalized malignancy, or who are being treated with alkylating agents, antimetabolites, radiation, or large amounts of corticosteroids.17
Because rabies vaccine is formulated with inactivated virus, it does not represent a danger to immunocompromised persons and may be administered to such persons using the standard recommended doses and schedule (Table 157-7). However, a five-dose schedule should be used in immunocompromised persons.17
The recommendations for the use of HRIG are the same for immunocompromised and immunocompetent persons. However, corticosteroids, antimalarials, other immunosuppressive agents, and immunosuppressive illnesses can interfere with the development of active immunity and predispose the patient to developing rabies. Immunosuppressive agents should not be administered during postexposure prophylaxis, unless they are essential for the treatment of other conditions. When rabies postexposure prophylaxis is administered to persons receiving steroids or other immunosuppressive therapy, it is especially important that serum be tested for rabies antibody to ensure that an adequate response has developed.12 To confirm the adequacy of the immune response, serum collected 1 to 24 weeks after the postexposure prophylaxis course should completely neutralize challenge virus at a 1:5 serum dilution, as measured by a rapid fluorescent focus inhibition test.12 If no accepTable antibody response is detected, consult an infectious disease expert and appropriate public health officials.
Preexposure prophylaxis is recommended for certain international travelers based on the local incidence of rabies in the countries to be visited, the availability of appropriate antirabies biologicals, and the intended travel activity.21,22 Such persons include veterinarians, animal handlers, field biologists, spelunkers, missionaries, and certain laboratory workers. Chloroquine phosphate (and possibly other structurally related antimalarials such as mefloquine, which is administered for malaria chemoprophylaxis) may interfere with the antibody response to intradermal rabies vaccine administered for preexposure prophylaxis. The IM route, not the intradermal route, should be used for people taking chloroquine concurrently (the intradermal route is not approved for use in the United States); ideally, the rabies preexposure vaccination series should be completed before beginning chloroquine.
Between 2001 and June 2010, six persons died in the United States from rabies after having been bitten by a dog (another died after being bitten by a fox) while visiting a foreign country. For this reason, all persons who have returned from abroad should be questioned regarding whether they received an animal bite or scratch in an area with endemic rabies. Persons bitten or scratched by an animal in an area with endemic rabies should receive appropriate postexposure prophylaxis if the injury has occurred within the known incubation period (which may rarely extend up to 5 or more years).
U.S. citizens and residents who are exposed to rabies while traveling in countries where rabies is endemic may sometimes receive postexposure prophylaxis with regimens or biologicals that are not used in the United States. If postexposure prophylaxis is begun outside the United States using a regimen or biological of nerve tissue origin not approved by the U.S. Food and Drug Administration, it may be necessary to provide additional treatment when the patient reaches the United States.12 State and local health departments should be contacted for specific advice in such cases. The major modification used abroad, usually in an attempt to reduce cost, is the substitution of various schedules for intradermal injection or the use of vaccines not approved by the U.S. Food and Drug Administration.
Adverse pregnancy outcomes or fetal abnormalities have not been associated with rabies vaccination. Because of the potential consequences of inadequately treated rabies exposure and because adverse events have not been associated with rabies postexposure prophylaxis during pregnancy, pregnancy is not considered a contraindication to rabies postexposure prophylaxis or HRIG.12 If there is substantial risk of exposure to rabies, preexposure prophylaxis may also be indicated during pregnancy.
The dose of rabies vaccine for preexposure and postexposure prophylaxis is the same in infants and children as in adults (Table 157-7).12 The dose of HRIG for postexposure prophylaxis is based on actual body weight. For small children with multiple bites, the calculated dose of HRIG may be insufficient to infiltrate all wounds. However, sterile saline can be used to dilute the volume twofold or threefold to permit thorough infiltration.21