Mayo Clin Proc. 2004;79:671-676 671 © 2004 Mayo Foundation for Medical Education and Research Concise Review for Clinicians Overview, Prevention, and Treatment of Rabies DANIEL G. HANKINS, MD, AND JULIA A. ROSEKRANS, MD From the Department of Emergency Medicine (D.G.H., J.A.R.) and Division of Pediatric Emergency Medicine (J.A.R.), Mayo Clinic Col- lege of Medicine, Rochester, Minn. A question-and-answer section appears at the end of this article. Address reprint requests and correspondence to Daniel G. Hankins, MD, Department of Emergency Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: dhankins @mayo.edu). CDC = Centers for Disease Control and Prevention; CNS = central nervous system; RIG = rabies immune globulin; RPEP = rabies postexposure prophylaxis Rabies is a uniformly fatal viral encephalitis that causes 30,000 to 70,000 deaths worldwide each year. Prevention is the primary approach to the disease. In the United States, 25,000 to 40,000 people are treated annually for exposure to rabid or potentially rabid animals at a per-patient cost exceeding $1000. Rabies is transmitted usually by saliva from infected animal bites. However, recent findings that rabies can be transmitted from bats to humans by rela- tively casual contact has resulted in dramatic changes in guidelines from the Centers for Disease Control and Pre- vention for postexposure prophylaxis. We review the 5 clinical stages of rabies, current methods of diagnosis, and prevention in animal reservoirs and in humans. We also discuss the use of rabies immune globulin and active and passive vaccinations for preexposure prophylaxis and postexposure treatment of rabies. Human exposure to ra- bies will always be a possibility, but methods to prevent the disease both before and after exposure to the virus are safe and readily available. Mayo Clin Proc. 2004;79:671-676 R abies is one of the oldest diseases known in recorded human history. The term rabies has been variously attributed to derivation from the Sanskrit rabhas (“to rage”) or the Latin rabere (“to rave”). Rabies was referred to in the Eshuma Code in Babylon more than 4000 years ago. Modern literature (eg, Old Yeller, To Kill a Mocking- bird, and Cujo) is replete with the horrors of this ancient illness. For the vast majority of human existence, a bite from a rabid animal was uniformly fatal. Because of fear of the disease, persons bitten by a rabid animal frequently committed suicide. The original rabies vaccine, developed by Louis Pasteur in 1885, dramatically changed the natural history of rabid contact, at least in the developed world. Despite that monumental development 120 years ago and the current availability of 3 effective vaccines, the World Health Organization estimates that between 30,000 and 70,000 people die worldwide of rabies every year. Contrast this with the United States’ death rate of 1 to 3 fatal human cases per year during the past 20 years. 1 THE VIRUS Rabies is caused by a bullet-shaped RNA rhabdovirus that is a member of the Rhabdoviridae family, genus Lyssa- virus. Previously, a single virus type was believed respon- sible for all rabies. The discovery of rabies-related viruses such as Lagos bat virus, Mokola virus, Duvenhage virus, and European and Australian bat viruses, also in the genus Lyssavirus, seriously challenged this view. Modern tech- niques of antigen detection have shown that several viruses and at least 6 serotypes in this genus cause diseases clini- cally related to rabies. Also, it is possible to tell by genetic sequencing that an infected human case originated, for example, from a silver-haired bat or a raccoon. 2-5 PATHOGENESIS Generally, rabies is transmitted by saliva from infected animal bites but may also be transmitted by scratches, secretions that contaminate mucus membranes, aerosolized virus that enters the respiratory tract, and corneal trans- plants. Since 1980, most human cases in the United States have not involved obvious bite wounds, but rather, less direct mechanisms of transmission. Guidelines from the Centers for Disease Control and Prevention (CDC) for postexposure rabies prophylaxis for humans who have had contact with a bat (see “Prevention” section) have changed dramatically in the past few years, after it became obvious that rabies could be transmitted from bats to humans by relatively casual contact. 6 The rabies virus has a predilection for nerve tissue and spreads along peripheral nerves and possibly muscle fibers 7 from the contact site to the central nervous system (CNS), causing encephalomyelitis. Initial symptoms are typical of a nonspecific viral syndrome, with fever, malaise, and headache, which progress to anxiety, agitation, and de- lirium. One clue for the clinician is tingling at the site of the bite during the first few days after contact, a consistent For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Overview, Prevention, and Treatment of Rabies
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Overview, Prevention, and Treatment of RabiesMayo Clin Proc, May 2004, Vol 79 Overview, Prevention, and Treatment of Rabies 671
Mayo Clin Proc. 2004;79:671-676 671 © 2004 Mayo Foundation for Medical Education and Research
Concise Review for Clinicians
DANIEL G. HANKINS, MD, AND JULIA A. ROSEKRANS, MD
From the Department of Emergency Medicine (D.G.H., J.A.R.) and Division of Pediatric Emergency Medicine (J.A.R.), Mayo Clinic Col- lege of Medicine, Rochester, Minn.
A question-and-answer section appears at the end of this article.
Address reprint requests and correspondence to Daniel G. Hankins, MD, Department of Emergency Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: dhankins @mayo.edu).
CDC = Centers for Disease Control and Prevention; CNS = central nervous system; RIG = rabies immune globulin; RPEP = rabies postexposure prophylaxis
Rabies is a uniformly fatal viral encephalitis that causes 30,000 to 70,000 deaths worldwide each year. Prevention is the primary approach to the disease. In the United States, 25,000 to 40,000 people are treated annually for exposure to rabid or potentially rabid animals at a per-patient cost exceeding $1000. Rabies is transmitted usually by saliva from infected animal bites. However, recent findings that rabies can be transmitted from bats to humans by rela- tively casual contact has resulted in dramatic changes in guidelines from the Centers for Disease Control and Pre- vention for postexposure prophylaxis. We review the 5 clinical stages of rabies, current methods of diagnosis, and
prevention in animal reservoirs and in humans. We also discuss the use of rabies immune globulin and active and passive vaccinations for preexposure prophylaxis and postexposure treatment of rabies. Human exposure to ra- bies will always be a possibility, but methods to prevent the disease both before and after exposure to the virus are safe and readily available.
Mayo Clin Proc. 2004;79:671-676
Rabies is one of the oldest diseases known in recorded human history. The term rabies has been variously
attributed to derivation from the Sanskrit rabhas (“to rage”) or the Latin rabere (“to rave”). Rabies was referred to in the Eshuma Code in Babylon more than 4000 years ago. Modern literature (eg, Old Yeller, To Kill a Mocking- bird, and Cujo) is replete with the horrors of this ancient illness. For the vast majority of human existence, a bite from a rabid animal was uniformly fatal. Because of fear of the disease, persons bitten by a rabid animal frequently committed suicide. The original rabies vaccine, developed by Louis Pasteur in 1885, dramatically changed the natural history of rabid contact, at least in the developed world. Despite that monumental development 120 years ago and the current availability of 3 effective vaccines, the World Health Organization estimates that between 30,000 and 70,000 people die worldwide of rabies every year. Contrast this with the United States’ death rate of 1 to 3 fatal human cases per year during the past 20 years.1
THE VIRUS Rabies is caused by a bullet-shaped RNA rhabdovirus that is a member of the Rhabdoviridae family, genus Lyssa- virus. Previously, a single virus type was believed respon-
sible for all rabies. The discovery of rabies-related viruses such as Lagos bat virus, Mokola virus, Duvenhage virus, and European and Australian bat viruses, also in the genus Lyssavirus, seriously challenged this view. Modern tech- niques of antigen detection have shown that several viruses and at least 6 serotypes in this genus cause diseases clini- cally related to rabies. Also, it is possible to tell by genetic sequencing that an infected human case originated, for example, from a silver-haired bat or a raccoon.2-5
PATHOGENESIS Generally, rabies is transmitted by saliva from infected animal bites but may also be transmitted by scratches, secretions that contaminate mucus membranes, aerosolized virus that enters the respiratory tract, and corneal trans- plants. Since 1980, most human cases in the United States have not involved obvious bite wounds, but rather, less direct mechanisms of transmission. Guidelines from the Centers for Disease Control and Prevention (CDC) for postexposure rabies prophylaxis for humans who have had contact with a bat (see “Prevention” section) have changed dramatically in the past few years, after it became obvious that rabies could be transmitted from bats to humans by relatively casual contact.6
The rabies virus has a predilection for nerve tissue and spreads along peripheral nerves and possibly muscle fibers7
from the contact site to the central nervous system (CNS), causing encephalomyelitis. Initial symptoms are typical of a nonspecific viral syndrome, with fever, malaise, and headache, which progress to anxiety, agitation, and de- lirium. One clue for the clinician is tingling at the site of the bite during the first few days after contact, a consistent
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Overview, Prevention, and Treatment of Rabies Mayo Clin Proc, May 2004, Vol 79672
symptom of a rabid bite. The virus then spreads from the CNS throughout the peripheral nervous system, especially to highly innervated areas such as salivary glands. This causes hypersalivation—“frothing at the mouth”—and spasm of the pharyngeal muscles at the sound, sight, or taste of water leading to hydrophobia. The disease progresses inexorably to generalized nervous system fail- ure and death.
CLINICAL FEATURES Rabies is a uniformly fatal disease once clinical symptoms manifest. Only 6 documented cases exist of survival after onset of clinical rabies; all these patients had received either preexposure prophylaxis or expeditious postex- posure prophylaxis after the rabid contact and before the patients had established clinical disease. Obviously, to con- sider the possibility of rabies at this stage requires a high index of suspicion and a thorough patient history. The remarkable bat-associated cases reported by the CDC dur- ing the past few years have shown that often a bat contact was missed because it was considered inconsequential by family or friends.2-4
Rabies presents with 1 of 2 clinical features. Encepha- litic (furious) rabies (80%-85% of cases) has the classic presentation with hydrophobia, pharyngeal spasms, and hyperactivity leading to paralysis, coma, and death. The paralytic form is much less common.
Rabies progresses through 5 clinical stages with much variability, depending on extent of bites, amount of secre- tion encountered, and proximity to the CNS, ie, disease transmitted through bites close to the brain will progress faster than disease transmitted through bites on the lower extremities.
Incubation—ranges from 10 days to 1 year (average, 20- 60 days).
Prodrome—occurs 2 to 10 days postexposure and lasts 1 day to 2 weeks. This stage is characterized by non- specific flulike symptoms, including malaise, anorexia, irritability, low-grade fever, headache, nausea, vomiting; paresthesia, pain, or numbness may be present at the bite site.
Acute neurologic syndrome—occurs 2 to 7 days after onset of prodrome. This syndrome includes dysarthria, dys- phagia, excessive salivation, diplopia, vertigo, nystagmus, restlessness, agitation, visual or auditory hallucinations, manic behavior alternating with lethargy, hydrophobia sec- ondary to painful contractions of pharyngeal muscles, poly- neuritis; hyperactive deep tendon reflexes with positive Babinski signs and nuchal rigidity often are present.
Coma—occurs 7 to 10 days after onset of acute neuro- logic syndrome. This stage is characterized by hydropho- bia, prolonged apnea, and generalized flaccid paralysis that
can intensify as in Guillain-Barré syndrome, seizures, and coma with ultimate respiratory and vascular collapse.
Death—may follow 2 to 3 days after onset of paralysis but may be delayed by life-support equipment. Recovery is rare.
Rabies can be diagnosed in humans before death by observation of virus-specific fluorescent material in skin biopsy specimens, isolation of the virus from patient saliva, or by the presence of antirabies antibodies in the serum or cerebrospinal fluid of patients who have not been immu- nized. Unfortunately, once the patient is symptomatic, use of antirabies vaccine or rabies immune globulin (RIG) does not improve prognosis, and treatment consists entirely of supportive care.
ANIMAL RESERVOIRS Rabies is found throughout the United States except for the islands of Hawaii. Several countries, most of which are islands, are rabies free, including the British Isles, New Zealand, Japan, Taiwan, many of the Caribbean islands, Sweden, Norway, and Spain. The fact that these countries remain free of rabies is a tribute to the stringency of their quarantine laws for imported animals. Australia was at one time believed to be rabies free, but bat-transmitted rabies is now endemic there.
In developed countries, the pattern of animal transmis- sion has dramatically changed during the past 50 years. Domesticated animals that transmit rabies (dogs, cats, cattle) account for only 10% of human exposures, whereas wild animals account for the other 90%, with skunks, foxes, raccoons, and bats being the most prominent. Dogs are the primary agent in nondeveloped countries.
It should be assumed that almost any warm-blooded animal might be carrying rabies. However, small rodents (gerbils, chipmunks, guinea pigs, squirrels, rats, and mice) and lagomorphs (rabbits and hares) in general do not carry rabies because they usually cannot survive an initial attack by a rabid animal. No documented case of human rabies has ever been traced to one of these animals in the United States; however, there are anecdotal reports of rabies trans- mitted by rats in Thailand8 and by bandicoots in Sri Lanka. Woodchucks (groundhogs), which are large rodents, can carry rabies. Beavers also have been reported to carry rabies.5
Animal carriers may vary by region or state. If there is a question, the state health department should be contacted. Also, animal carriers vary around the world; mongooses and antelope are common sources in Africa, for instance.
The rabies endemic to the United States results in 25,000 to 40,000 people being treated annually for expo- sure to rabid or potentially rabid animals, especially ones that escape after biting (usually dogs). The CDC estimates
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, May 2004, Vol 79 Overview, Prevention, and Treatment of Rabies 673
that a course of RIG and 5 doses of vaccine given during a 4-week period typically exceeds $1000. The vaccine course cost per human life saved from rabies ranges from approximately $10,000 to $100 million, depending on the nature of the exposure and the probability of rabies in a region.9
PREVENTION Rabies cannot be treated; therefore, efforts must be focused on preventing the disease. Disease-prevention measures are aimed at the animals that can transmit rabies or can include postexposure treatment of a person.
The incidence of rabies in humans in the United States has decreased dramatically with the introduction of communitywide rabies immunization for domestic ani- mals. Although most domestic animals in urban areas are immunized repeatedly, this is not always the case for all farm animals or for feral animals living on the fringes of domestic society.10
Rabies-prevention measures are the responsibility of animal owners. Maintaining immunizations for domestic pets not only protects the pet but also provides some pro- tection for pet owners and wild animals. Pets should be supervised so that they do not come into contact with wild animals. Communities maintain animal-control agencies to remove stray or wild animals to decrease the risk of disease.
Rabies continues to be found in wild animals in North America. Education about avoiding contact with wild ani- mals is an important public health measure in reducing risk of rabies exposure. Raccoons, skunks, foxes, and coyotes can be enjoyed from a distance, but they should not be attracted intentionally or adopted. The first recorded hu- man death from genetically sequenced raccoon rabies was reported recently. Aerial vaccination programs have re- duced the incidence of rabies in coyotes in southern Texas and raccoons in the Atlantic states; however, any person who is bitten by a wild animal anywhere in North Amer- ica should be considered at extremely high risk of rabies infection.11-15
Bats are the major source of human rabies in the United States.16 For many patients in whom nucleotide analysis shows that the rabies virus strain is of bat origin, no history of an actual bat bite can be obtained. This may be because the bat bite is extremely small, the patient does not report a bite to anyone and can no longer give the history, or the virus is spread through aerosol transmission.17,18
Preventing rabies transmission by bats needs to be ad- dressed through education about bat behavior. Homes should be bat-proofed by covering ventilation openings with screens. Because bats are nocturnal, any daytime bat activity should be considered extremely suspicious. Direct
contact with bats should be avoided. The CDC recom- mends postexposure rabies prophylaxis for anyone who has contact with a bat, even if there has been no bite. Any person who awakens from sleep and finds a bat in the room should be immunized. Some may consider such immuniza- tion to be overtreatment; however, rabies is uniformly fatal, and effective treatment is available. Treatment is costly, but no rabies-exposed patient wants to wait to see whether clinical disease develops before being treated.
PREEXPOSURE PROPHYLAXIS Preexposure prophylactic immunization is recommended for people who are likely to be exposed to rabid animals. Veterinarians, animal handlers, and laboratory personnel should consider routine immunization. Also, people travel- ing to areas where dog rabies is endemic and who will not have easy access to medical care should consider immuni- zation before traveling.19
A person who was previously immunized and who has had a potential rabies exposure should receive 2 intramus- cular doses of vaccine, the first dose as soon as possible after exposure and the other 3 days later. “Previously im- munized” persons include those who received 1 of the vaccines according to recommended US schedules or those who had a documented adequate rabies antibody titer after other vaccination administration. RIG is unnecessary be- cause of the anamnestic response in previously vaccinated persons. Routine serologic testing after booster vaccination is not recommended because of the uniformity of an anti- body response.
POSTEXPOSURE TREATMENT Wound Care
After an animal has bitten a person, the bite should be cleaned extensively with soap and water to help reduce the risk of bacterial infection. Povidone solutions or 70% alco- hol may reduce viral transmission from a bite. Cosmetic repair of a bite wound should be assessed; however, closing a wound may increase the risk of bacterial infection.20
Immunization against rabies should be based on assess- ment of the rabies risk in the animal that caused the bite (Table 121).
In general, a bite from a domestic animal that has been reliably immunized does not represent a high risk of rabies and does not necessitate rabies treatment unless the ani- mal’s behavior is unusual. Animals that are at low risk for rabies can be observed for signs of behavioral abnormali- ties for a 10-day period. If the animal shows abnormal behavior, its saliva would be infectious, and killing the animal is warranted.
In developing countries, immunization of domestic ani- mals may not be current. Therefore, all bites should be
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Overview, Prevention, and Treatment of Rabies Mayo Clin Proc, May 2004, Vol 79674
Table 1. Indications for Rabies Immunization*
Evaluation and disposition Postexposure prophylaxis Animal type of animal and recommendations
Dog, cat, ferret Healthy and available for 10-day Use prophylaxis only if animal observation develops signs of rabies†
Rabid or suspected of being rabid Treat immediately with rabies vaccine and RIG
Unknown or escaped Consult public health officials
Bat, skunk, raccoon, fox, and Regard as rabid unless geographic Treat immediately with rabies most other carnivores; area is known to be rabies free or vaccine and RIG woodchuck until animal is proved rabies free
by laboratory tests‡
Livestock, rodents, lagomorphs (rabbits and hares) Consider individually Consult public health officials
*RIG = rabies immune globulin. †During the 10-day observation period, at the first sign of rabies in the biting animal, treatment with RIG and
rabies vaccine should be initiated. The suspected animal should be killed and tested. ‡The animal should be killed and tested as soon as possible. Holding for observation is not recommended.
Immunization can be discontinued if immunofluorescent test results of the animal are negative.21
considered potentially rabid, and treatment should be started immediately after any dog bite, whether the animal is domestic or wild.
If a person is bitten by a wild or unimmunized animal and the animal can be killed and examined for possible rabies, the patient should be immunized immediately and then treatment continued on the basis of test results. Unfor- tunately, the animal is unavailable in many cases, and every bite by a wild animal must be considered rabid.
Immunoprophylaxis Administration of rabies postexposure prophylaxis
(RPEP) is a medical urgency but not a medical emergency. The need for rabies prevention should be evaluated care- fully. Regional public health officials are helpful in mak- ing the decision to initiate prophylaxis. The Advisory Committee on Immunization Practices has comprehensive guidelines for RPEP. A review of actual RPEP practice in urban emergency departments found that RPEP was initiated inappropriately in many cases but was withheld inappropriately in even more cases that met criteria for immunization.22,23
When RPEP is indicated, both passive and active vacci- nation always should be given. The combination of rabies immunoglobulin and rabies vaccine should be used for both saliva-contaminated bites and for nonbite exposures.
The incubation period in humans from virus exposure to onset of clinical disease is believed to average from 4 to 6 weeks but has been reported to range from 5 days to more than 1 year. Immunization should be initiated as quickly as possible after potential rabies exposure.21
Passive Vaccination.—RIG is a solution of globulins dried from the plasma or serum of selected adult human donors who have been immunized with rabies vaccine and
have developed high titers of rabies antibody. RIG gener- ally contains 10% to 18% protein of which 80% or more is monomeric immunoglobulin G. RIG is administered to previously unimmunized people so that passive antibodies are present until the person begins making active antibod- ies to the vaccine. RIG should not be given more than 7 days after initiation of the vaccine because RIG may de- crease a person’s own antibody response.
RIG is given in a single dose of 20 IU/kg body weight. This dose should not be exceeded because higher doses may decrease antibody response to the vaccine.
If there is a bite wound and it is in an anatomical location that allows infiltration of the wound, the full RIG dose should be injected directly into and around the wound. If the exposure is a nonbite event or if the bite is too small or on an area such as a fingertip where infiltration is unfea- sible, the entire RIG dose can be given intramuscularly, usually in the buttocks.
The most common complications of RIG are pain and soreness at the injection site. Caution must be taken to avoid intravenous administration because anaphylaxis can occur. If the patient had a previous reaction to any human immunoglobulin, the patient’s history must be reviewed carefully before RIG is given. If the patient has received any other live virus vaccines, immune response may be blunted by RIG.
Active Vaccination.—Three rabies vaccines are cur- rently available in the United States: rabies vaccine ad- sorbed, human diploid cell rabies vaccine, and purified chick embryo cell vaccine; all 3 are inactivated virus vac- cines. The production of specific antibodies against rabies virus requires about 7 to 10 days to develop. The vaccina- tion series needed to achieve protective levels of antibody against rabies consists of five 1-mL doses given in the
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, May 2004, Vol 79 Overview, Prevention, and Treatment of Rabies 675
deltoid area. After the initial vaccine is given, the 4 subse- quent doses should be given on days 3, 7,…
Mayo Clin Proc. 2004;79:671-676 671 © 2004 Mayo Foundation for Medical Education and Research
Concise Review for Clinicians
DANIEL G. HANKINS, MD, AND JULIA A. ROSEKRANS, MD
From the Department of Emergency Medicine (D.G.H., J.A.R.) and Division of Pediatric Emergency Medicine (J.A.R.), Mayo Clinic Col- lege of Medicine, Rochester, Minn.
A question-and-answer section appears at the end of this article.
Address reprint requests and correspondence to Daniel G. Hankins, MD, Department of Emergency Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: dhankins @mayo.edu).
CDC = Centers for Disease Control and Prevention; CNS = central nervous system; RIG = rabies immune globulin; RPEP = rabies postexposure prophylaxis
Rabies is a uniformly fatal viral encephalitis that causes 30,000 to 70,000 deaths worldwide each year. Prevention is the primary approach to the disease. In the United States, 25,000 to 40,000 people are treated annually for exposure to rabid or potentially rabid animals at a per-patient cost exceeding $1000. Rabies is transmitted usually by saliva from infected animal bites. However, recent findings that rabies can be transmitted from bats to humans by rela- tively casual contact has resulted in dramatic changes in guidelines from the Centers for Disease Control and Pre- vention for postexposure prophylaxis. We review the 5 clinical stages of rabies, current methods of diagnosis, and
prevention in animal reservoirs and in humans. We also discuss the use of rabies immune globulin and active and passive vaccinations for preexposure prophylaxis and postexposure treatment of rabies. Human exposure to ra- bies will always be a possibility, but methods to prevent the disease both before and after exposure to the virus are safe and readily available.
Mayo Clin Proc. 2004;79:671-676
Rabies is one of the oldest diseases known in recorded human history. The term rabies has been variously
attributed to derivation from the Sanskrit rabhas (“to rage”) or the Latin rabere (“to rave”). Rabies was referred to in the Eshuma Code in Babylon more than 4000 years ago. Modern literature (eg, Old Yeller, To Kill a Mocking- bird, and Cujo) is replete with the horrors of this ancient illness. For the vast majority of human existence, a bite from a rabid animal was uniformly fatal. Because of fear of the disease, persons bitten by a rabid animal frequently committed suicide. The original rabies vaccine, developed by Louis Pasteur in 1885, dramatically changed the natural history of rabid contact, at least in the developed world. Despite that monumental development 120 years ago and the current availability of 3 effective vaccines, the World Health Organization estimates that between 30,000 and 70,000 people die worldwide of rabies every year. Contrast this with the United States’ death rate of 1 to 3 fatal human cases per year during the past 20 years.1
THE VIRUS Rabies is caused by a bullet-shaped RNA rhabdovirus that is a member of the Rhabdoviridae family, genus Lyssa- virus. Previously, a single virus type was believed respon-
sible for all rabies. The discovery of rabies-related viruses such as Lagos bat virus, Mokola virus, Duvenhage virus, and European and Australian bat viruses, also in the genus Lyssavirus, seriously challenged this view. Modern tech- niques of antigen detection have shown that several viruses and at least 6 serotypes in this genus cause diseases clini- cally related to rabies. Also, it is possible to tell by genetic sequencing that an infected human case originated, for example, from a silver-haired bat or a raccoon.2-5
PATHOGENESIS Generally, rabies is transmitted by saliva from infected animal bites but may also be transmitted by scratches, secretions that contaminate mucus membranes, aerosolized virus that enters the respiratory tract, and corneal trans- plants. Since 1980, most human cases in the United States have not involved obvious bite wounds, but rather, less direct mechanisms of transmission. Guidelines from the Centers for Disease Control and Prevention (CDC) for postexposure rabies prophylaxis for humans who have had contact with a bat (see “Prevention” section) have changed dramatically in the past few years, after it became obvious that rabies could be transmitted from bats to humans by relatively casual contact.6
The rabies virus has a predilection for nerve tissue and spreads along peripheral nerves and possibly muscle fibers7
from the contact site to the central nervous system (CNS), causing encephalomyelitis. Initial symptoms are typical of a nonspecific viral syndrome, with fever, malaise, and headache, which progress to anxiety, agitation, and de- lirium. One clue for the clinician is tingling at the site of the bite during the first few days after contact, a consistent
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Overview, Prevention, and Treatment of Rabies Mayo Clin Proc, May 2004, Vol 79672
symptom of a rabid bite. The virus then spreads from the CNS throughout the peripheral nervous system, especially to highly innervated areas such as salivary glands. This causes hypersalivation—“frothing at the mouth”—and spasm of the pharyngeal muscles at the sound, sight, or taste of water leading to hydrophobia. The disease progresses inexorably to generalized nervous system fail- ure and death.
CLINICAL FEATURES Rabies is a uniformly fatal disease once clinical symptoms manifest. Only 6 documented cases exist of survival after onset of clinical rabies; all these patients had received either preexposure prophylaxis or expeditious postex- posure prophylaxis after the rabid contact and before the patients had established clinical disease. Obviously, to con- sider the possibility of rabies at this stage requires a high index of suspicion and a thorough patient history. The remarkable bat-associated cases reported by the CDC dur- ing the past few years have shown that often a bat contact was missed because it was considered inconsequential by family or friends.2-4
Rabies presents with 1 of 2 clinical features. Encepha- litic (furious) rabies (80%-85% of cases) has the classic presentation with hydrophobia, pharyngeal spasms, and hyperactivity leading to paralysis, coma, and death. The paralytic form is much less common.
Rabies progresses through 5 clinical stages with much variability, depending on extent of bites, amount of secre- tion encountered, and proximity to the CNS, ie, disease transmitted through bites close to the brain will progress faster than disease transmitted through bites on the lower extremities.
Incubation—ranges from 10 days to 1 year (average, 20- 60 days).
Prodrome—occurs 2 to 10 days postexposure and lasts 1 day to 2 weeks. This stage is characterized by non- specific flulike symptoms, including malaise, anorexia, irritability, low-grade fever, headache, nausea, vomiting; paresthesia, pain, or numbness may be present at the bite site.
Acute neurologic syndrome—occurs 2 to 7 days after onset of prodrome. This syndrome includes dysarthria, dys- phagia, excessive salivation, diplopia, vertigo, nystagmus, restlessness, agitation, visual or auditory hallucinations, manic behavior alternating with lethargy, hydrophobia sec- ondary to painful contractions of pharyngeal muscles, poly- neuritis; hyperactive deep tendon reflexes with positive Babinski signs and nuchal rigidity often are present.
Coma—occurs 7 to 10 days after onset of acute neuro- logic syndrome. This stage is characterized by hydropho- bia, prolonged apnea, and generalized flaccid paralysis that
can intensify as in Guillain-Barré syndrome, seizures, and coma with ultimate respiratory and vascular collapse.
Death—may follow 2 to 3 days after onset of paralysis but may be delayed by life-support equipment. Recovery is rare.
Rabies can be diagnosed in humans before death by observation of virus-specific fluorescent material in skin biopsy specimens, isolation of the virus from patient saliva, or by the presence of antirabies antibodies in the serum or cerebrospinal fluid of patients who have not been immu- nized. Unfortunately, once the patient is symptomatic, use of antirabies vaccine or rabies immune globulin (RIG) does not improve prognosis, and treatment consists entirely of supportive care.
ANIMAL RESERVOIRS Rabies is found throughout the United States except for the islands of Hawaii. Several countries, most of which are islands, are rabies free, including the British Isles, New Zealand, Japan, Taiwan, many of the Caribbean islands, Sweden, Norway, and Spain. The fact that these countries remain free of rabies is a tribute to the stringency of their quarantine laws for imported animals. Australia was at one time believed to be rabies free, but bat-transmitted rabies is now endemic there.
In developed countries, the pattern of animal transmis- sion has dramatically changed during the past 50 years. Domesticated animals that transmit rabies (dogs, cats, cattle) account for only 10% of human exposures, whereas wild animals account for the other 90%, with skunks, foxes, raccoons, and bats being the most prominent. Dogs are the primary agent in nondeveloped countries.
It should be assumed that almost any warm-blooded animal might be carrying rabies. However, small rodents (gerbils, chipmunks, guinea pigs, squirrels, rats, and mice) and lagomorphs (rabbits and hares) in general do not carry rabies because they usually cannot survive an initial attack by a rabid animal. No documented case of human rabies has ever been traced to one of these animals in the United States; however, there are anecdotal reports of rabies trans- mitted by rats in Thailand8 and by bandicoots in Sri Lanka. Woodchucks (groundhogs), which are large rodents, can carry rabies. Beavers also have been reported to carry rabies.5
Animal carriers may vary by region or state. If there is a question, the state health department should be contacted. Also, animal carriers vary around the world; mongooses and antelope are common sources in Africa, for instance.
The rabies endemic to the United States results in 25,000 to 40,000 people being treated annually for expo- sure to rabid or potentially rabid animals, especially ones that escape after biting (usually dogs). The CDC estimates
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, May 2004, Vol 79 Overview, Prevention, and Treatment of Rabies 673
that a course of RIG and 5 doses of vaccine given during a 4-week period typically exceeds $1000. The vaccine course cost per human life saved from rabies ranges from approximately $10,000 to $100 million, depending on the nature of the exposure and the probability of rabies in a region.9
PREVENTION Rabies cannot be treated; therefore, efforts must be focused on preventing the disease. Disease-prevention measures are aimed at the animals that can transmit rabies or can include postexposure treatment of a person.
The incidence of rabies in humans in the United States has decreased dramatically with the introduction of communitywide rabies immunization for domestic ani- mals. Although most domestic animals in urban areas are immunized repeatedly, this is not always the case for all farm animals or for feral animals living on the fringes of domestic society.10
Rabies-prevention measures are the responsibility of animal owners. Maintaining immunizations for domestic pets not only protects the pet but also provides some pro- tection for pet owners and wild animals. Pets should be supervised so that they do not come into contact with wild animals. Communities maintain animal-control agencies to remove stray or wild animals to decrease the risk of disease.
Rabies continues to be found in wild animals in North America. Education about avoiding contact with wild ani- mals is an important public health measure in reducing risk of rabies exposure. Raccoons, skunks, foxes, and coyotes can be enjoyed from a distance, but they should not be attracted intentionally or adopted. The first recorded hu- man death from genetically sequenced raccoon rabies was reported recently. Aerial vaccination programs have re- duced the incidence of rabies in coyotes in southern Texas and raccoons in the Atlantic states; however, any person who is bitten by a wild animal anywhere in North Amer- ica should be considered at extremely high risk of rabies infection.11-15
Bats are the major source of human rabies in the United States.16 For many patients in whom nucleotide analysis shows that the rabies virus strain is of bat origin, no history of an actual bat bite can be obtained. This may be because the bat bite is extremely small, the patient does not report a bite to anyone and can no longer give the history, or the virus is spread through aerosol transmission.17,18
Preventing rabies transmission by bats needs to be ad- dressed through education about bat behavior. Homes should be bat-proofed by covering ventilation openings with screens. Because bats are nocturnal, any daytime bat activity should be considered extremely suspicious. Direct
contact with bats should be avoided. The CDC recom- mends postexposure rabies prophylaxis for anyone who has contact with a bat, even if there has been no bite. Any person who awakens from sleep and finds a bat in the room should be immunized. Some may consider such immuniza- tion to be overtreatment; however, rabies is uniformly fatal, and effective treatment is available. Treatment is costly, but no rabies-exposed patient wants to wait to see whether clinical disease develops before being treated.
PREEXPOSURE PROPHYLAXIS Preexposure prophylactic immunization is recommended for people who are likely to be exposed to rabid animals. Veterinarians, animal handlers, and laboratory personnel should consider routine immunization. Also, people travel- ing to areas where dog rabies is endemic and who will not have easy access to medical care should consider immuni- zation before traveling.19
A person who was previously immunized and who has had a potential rabies exposure should receive 2 intramus- cular doses of vaccine, the first dose as soon as possible after exposure and the other 3 days later. “Previously im- munized” persons include those who received 1 of the vaccines according to recommended US schedules or those who had a documented adequate rabies antibody titer after other vaccination administration. RIG is unnecessary be- cause of the anamnestic response in previously vaccinated persons. Routine serologic testing after booster vaccination is not recommended because of the uniformity of an anti- body response.
POSTEXPOSURE TREATMENT Wound Care
After an animal has bitten a person, the bite should be cleaned extensively with soap and water to help reduce the risk of bacterial infection. Povidone solutions or 70% alco- hol may reduce viral transmission from a bite. Cosmetic repair of a bite wound should be assessed; however, closing a wound may increase the risk of bacterial infection.20
Immunization against rabies should be based on assess- ment of the rabies risk in the animal that caused the bite (Table 121).
In general, a bite from a domestic animal that has been reliably immunized does not represent a high risk of rabies and does not necessitate rabies treatment unless the ani- mal’s behavior is unusual. Animals that are at low risk for rabies can be observed for signs of behavioral abnormali- ties for a 10-day period. If the animal shows abnormal behavior, its saliva would be infectious, and killing the animal is warranted.
In developing countries, immunization of domestic ani- mals may not be current. Therefore, all bites should be
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Overview, Prevention, and Treatment of Rabies Mayo Clin Proc, May 2004, Vol 79674
Table 1. Indications for Rabies Immunization*
Evaluation and disposition Postexposure prophylaxis Animal type of animal and recommendations
Dog, cat, ferret Healthy and available for 10-day Use prophylaxis only if animal observation develops signs of rabies†
Rabid or suspected of being rabid Treat immediately with rabies vaccine and RIG
Unknown or escaped Consult public health officials
Bat, skunk, raccoon, fox, and Regard as rabid unless geographic Treat immediately with rabies most other carnivores; area is known to be rabies free or vaccine and RIG woodchuck until animal is proved rabies free
by laboratory tests‡
Livestock, rodents, lagomorphs (rabbits and hares) Consider individually Consult public health officials
*RIG = rabies immune globulin. †During the 10-day observation period, at the first sign of rabies in the biting animal, treatment with RIG and
rabies vaccine should be initiated. The suspected animal should be killed and tested. ‡The animal should be killed and tested as soon as possible. Holding for observation is not recommended.
Immunization can be discontinued if immunofluorescent test results of the animal are negative.21
considered potentially rabid, and treatment should be started immediately after any dog bite, whether the animal is domestic or wild.
If a person is bitten by a wild or unimmunized animal and the animal can be killed and examined for possible rabies, the patient should be immunized immediately and then treatment continued on the basis of test results. Unfor- tunately, the animal is unavailable in many cases, and every bite by a wild animal must be considered rabid.
Immunoprophylaxis Administration of rabies postexposure prophylaxis
(RPEP) is a medical urgency but not a medical emergency. The need for rabies prevention should be evaluated care- fully. Regional public health officials are helpful in mak- ing the decision to initiate prophylaxis. The Advisory Committee on Immunization Practices has comprehensive guidelines for RPEP. A review of actual RPEP practice in urban emergency departments found that RPEP was initiated inappropriately in many cases but was withheld inappropriately in even more cases that met criteria for immunization.22,23
When RPEP is indicated, both passive and active vacci- nation always should be given. The combination of rabies immunoglobulin and rabies vaccine should be used for both saliva-contaminated bites and for nonbite exposures.
The incubation period in humans from virus exposure to onset of clinical disease is believed to average from 4 to 6 weeks but has been reported to range from 5 days to more than 1 year. Immunization should be initiated as quickly as possible after potential rabies exposure.21
Passive Vaccination.—RIG is a solution of globulins dried from the plasma or serum of selected adult human donors who have been immunized with rabies vaccine and
have developed high titers of rabies antibody. RIG gener- ally contains 10% to 18% protein of which 80% or more is monomeric immunoglobulin G. RIG is administered to previously unimmunized people so that passive antibodies are present until the person begins making active antibod- ies to the vaccine. RIG should not be given more than 7 days after initiation of the vaccine because RIG may de- crease a person’s own antibody response.
RIG is given in a single dose of 20 IU/kg body weight. This dose should not be exceeded because higher doses may decrease antibody response to the vaccine.
If there is a bite wound and it is in an anatomical location that allows infiltration of the wound, the full RIG dose should be injected directly into and around the wound. If the exposure is a nonbite event or if the bite is too small or on an area such as a fingertip where infiltration is unfea- sible, the entire RIG dose can be given intramuscularly, usually in the buttocks.
The most common complications of RIG are pain and soreness at the injection site. Caution must be taken to avoid intravenous administration because anaphylaxis can occur. If the patient had a previous reaction to any human immunoglobulin, the patient’s history must be reviewed carefully before RIG is given. If the patient has received any other live virus vaccines, immune response may be blunted by RIG.
Active Vaccination.—Three rabies vaccines are cur- rently available in the United States: rabies vaccine ad- sorbed, human diploid cell rabies vaccine, and purified chick embryo cell vaccine; all 3 are inactivated virus vac- cines. The production of specific antibodies against rabies virus requires about 7 to 10 days to develop. The vaccina- tion series needed to achieve protective levels of antibody against rabies consists of five 1-mL doses given in the
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Mayo Clin Proc, May 2004, Vol 79 Overview, Prevention, and Treatment of Rabies 675
deltoid area. After the initial vaccine is given, the 4 subse- quent doses should be given on days 3, 7,…
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