AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Rabies is a viral infection of the central and peripheral nervous systems that causes encephalitis with or without paralysis; it is virtually uniformly fatal.

Epidemiology and transmission

Bat (avian) rabies appears to be widespread in the 49 continental states. Bat rabies has been implicated in most human rabies cases acquired domestically in the United States during the last 25 years.¹ Cases of rabies have been reported in humans exposed to aerosols of bat guano during recreational caving or to aerosolized laboratory strain virus. Recently, rabies has occurred secondary to virus transmission from infected transplanted solid organs in the United States.^{2, 3} Statistics compiled by the Centers for Disease Control and Prevention (CDC) in the United States confirm that most human deaths from rabies not associated with foreign travel are from bat strains of rabies.^{4, 5}

In the United States, terrestrial rabies is most common in raccoons on the eastern coast and in skunks, foxes, coyotes, and dogs on the Texas-Mexico border. Canine rabies and bat rabies are significant problems in Mexico and around the world.

Five antigenic variants of rabies strains are recognized in the United States. The single raccoon strain is the predominant strain (see Media file 1).^{6, 7} A single case of human rabies has resulted from the raccoon rabies strain in the United States.⁸

The only rodent in the United States that can carry rabies long enough to transmit to humans is the groundhog. Other small rodents (eg, squirrels, chipmunks, rats, mice) and lagomorphs (eg, rabbits, hares) usually die before being able to transmit rabies virus to humans, and human disease has never been transmitted by these mammals.

Domestic animals usually succumb to the virus strain predominant in their geographic region. Cats are the most common domestic animals reported by health departments as being rabid because of the high number of unvaccinated strays with possible contacts with bats and other mammals.^{9, 10}

Since 1980, most endemic rabies cases in humans in the United States have been associated with bat strains. Other cases have been associated with dog or animal bites in travelers returning from abroad, especially in countries where wild canine rabies is endemic. In other countries, canines are the most common source of rabies. Other animals, such as mongooses, jackals, ferrets, and domestic farm animals, may be common sources. Human-to-human transmission has only occurred with corneal and other organ transplants.^{3, 2} Transmission of virus in saliva through mucous membranes, open wounds, or scratches is possible but rarely documented.

Rabies-free areas of the world are recognized. The island nations of the Caribbean are free of terrestrial rabies but may have bat rabies.¹¹ Updates of this information can be found through the World Health Organization (WHO) and the CDC.

Pathophysiology

When the rabies virus enters muscles, it replicates locally and is then transported through peripheral sensory nerves to the spinal ganglia, where it replicates and travels up the spinal cord to the brain. The virus migrates to the gray matter of the brain and predominates in the neurons of the limbic system, midbrain, and hypothalamus. Efferent nerves transport virus to the acinar glands of the submaxillary salivary glands, where it achieves high concentrations.¹²

This transit time is presumably shorter if the initial wound is severe with a high load of virus and is proximal to the head. ^{13, 14}

The reported incubation period in human beings has ranged from as short as 5 days to as long as 7 years; average incubation is 1-3 months prior to onset of symptoms. In rare cases, human rabies with an extended incubation period (2-7 y) has been reported.^{15, 16}

Frequency

United States

During 1990-1998, 22 cases of human rabies were reported in the United States. Potential exposures are not uncommon in the United States; an estimated 20,000-30,000 people per year receive treatment for potential rabies exposures. Exact exposures can only be determined if an animal is submitted for testing.^{1, 17}

International

Worldwide, endemic countries with wild animal vectors may have death rates as high as 40,000-50,000 per year (eg, Asia, Africa).

Mortality/Morbidity

Rabies is 100% fatal if postexposure treatment is not administered. A single survivor who was treated with an intensive care protocol to induce a controlled coma has been reported in the United States.¹⁸ Since then, others have tried to repeat use of this intervention without success.¹⁹

Race

No racial predilection is observed.

Sex

Encounters with rabid animal vectors may be increased in males, who may have greater contact in certain geographic areas. Evidence to support this is found in data on dog bites, which are observed more frequently in males than females.

Age

No age predilection is noted.

CLINICAL

Section 3 of 11  

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History

• Identify the following in any suspected case of rabies virus exposure:
• • The nature of the interaction with the animal (eg, provoked attack or unexpected)
  • Strange animal behavior (eg, nocturnal animal out during the daytime)
  • Vaccination status of the animal for rabies⁹ (See Other Tests.)
• The 2 forms of rabies vary in nature of presentation between illness in the animal and possible human cases. Both forms progress to paralysis of pharyngeal and respiratory muscles, seizures, and coma with death in 1-3 weeks.
• • Most common in humans is the furious form with classic symptoms of paresthesias at the site of the bite, hypersalivation, and hydrophobia, including spasms and contractions of the neck muscles. This form is also common in cats.
  • Many other animals, including bats, exhibit dumb rabies (paralytic form).

Physical

Include the following in any examination of a patient who has been bitten by an animal:

• Localization and documentation of the extent of the wound
• Evidence of secondary complications, such as bacterial superinfection and tissue destruction
• Neurologic examination of a patient with rabies - May reveal altered mental status, anxiety, hyperactivity, and bizarre behaviors with interspersed calm periods
• Examination for autonomic instability - Hypertension, hypersalivation, hyperthermia, hyperventilation

Causes

• Rabies is caused by the rabies virus, of the genus Lyssavirus and family Rhabdoviridae.
• The bullet-shaped RNA virus has 3 major components: surface glycoprotein (G protein), outer envelope protein (M or matrix protein), and nucleocapsid.
• Rabies virus is transmitted by bite or saliva of an infected mammal.
• Any mammal can carry and potentially transmit the virus, but carnivorous species and bats are usually the agents of transmission.

DIFFERENTIALS

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Other Problems to be Considered

Other encephalitides (especially herpes simplex encephalitis because it is treatable)
Guillain-Barré syndrome, transverse myelitis, and poliomyelitis (Patients may present with similar paralytic features.)
Tetanus (Rigidity of tetanus contractions is more prolonged, with mental status usually normal.)
Epilepsy
Poisoning with atropinelike compounds
Pseudohydrophobia (hysterical reaction to animal bites)

WORKUP

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Other Tests

Diagnostic studies for rabies include the following:

• Brain biopsy with immunohistochemical or florescent antibody staining is definitive. Euthanize wild animals that have been captured after biting and have state health departments test the unfixed brain tissue.¹²
• In suspected human cases, perform skin biopsy from the nape of the neck or, less preferably, obtain a smear of corneal epithelial cells for similar specific stains.
• Rise in specific neutralizing antibodies on rapid fluorescent focus inhibition testing (RFFIT) is often not documented in true rabies cases because the victims succumb to the disease prior to mounting a response. Serologic testing is more useful to ascertain serostatus in immunized animals and humans.²⁰
• Viral culture of saliva, cerebrospinal fluid, and brain can also be performed in specialized laboratories. These tissue specimens can also be tested using polymerase chain reaction (PCR).

Procedures

• Wound debridement at the time of patient evaluation is essential, along with careful cleaning of the wound for longer than 10 minutes.
• Generally, leave wounds to heal by secondary intention.^{21, 20}

Histologic Findings

• General findings on pathology include cerebral congestion and inflammation typical of encephalitis.
• Immunohistochemical or fluorescent antibody staining of nervous tissue, usually of unfixed brain or skin biopsy specimens with sensory nerve endings, reveals deposition of virion in the cytoplasm.
• Negri bodies are observed in neurons on light microscopy and represent round cytoplasmic inclusions of assembling nucleocapsid. Only 70% of brain biopsy tissue exhibits this finding in human rabies encephalitis.
• Electron microscopy is more sensitive than light microscopy and reveals the characteristic bullet-shaped virion.

TREATMENT

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Medical Care

• Administer human rabies immunoglobulin (HRIG) to any person not previously vaccinated against rabies in a dose of 20 IU/kg (for adults and children). Apply as much of the dose as possible at the injury site and the remainder as a deep intramuscular injection in the gluteal area. HRIG may be administered as long as 7 days after the first dose of vaccine if it is not immediately available when the patient presents for evaluation.²⁰
• Equine rabies immunoglobulin may be available in other countries. Minimal adverse effects occur if it is in the purified form; however, if unpurified, it may cause serum sickness and anaphylaxis.
• Two different inactivated rabies vaccines are licensed and produced in the United States, as follows:
• • Human diploid cell vaccine (HDCV; Imovax) -  Usual dosing for postexposure prophylaxis to be administered as intramuscular (IM) injection
  • Purified chick embryo cell vaccine (PCEC; RabAvert) - Licensed in the United States in 1997 for IM use only
• Doses of all the vaccines for postexposure prophylaxis are 1 mL IM in deltoid or upper outer thigh in infants.
• The 5-dose schedule is the same for all 3 vaccine products, as follows: day 0, day 3, day 7, day 14, and day 28 postexposure.
• Postexposure antibody testing is not necessary in healthy individuals.
• Mild local and systemic adverse reactions to these vaccines and immunoglobulin may occur but are usually treatable with supportive care, antihistamines, and anti-inflammatory medications. Local pain, erythema, headache, nausea, and abdominal pain may occur. If prophylaxis is warranted, do not postpone or discontinue treatment because of mild adverse effects.
• Postexposure rabies prophylaxis for patients not previously vaccinated is as follows:
• • Local wound cleansing: Begin all postexposure treatment with immediate thorough cleansing for 10 minutes with soap and water.
  • HRIG: Administer 20 IU/kg with the full dose infiltrated at the wound and any remaining volume administered IM gluteally or at another other anatomic site distant from the site of vaccine administration.
  • Vaccine: Administer HDCV, RVA, or RabAvert at 1 mL IM (deltoid or thigh) on days 0, 3, 7, 14, and 28.
• Bite wound management involves the following:
• • Cleanse the wound with soap and water or preferably povidone/iodine solution for at least 10 minutes, with debridement of devitalized tissue as necessary. Failure of adequate cleansing has caused failure of passive and active immunoprophylaxis in human rabies cases.
  • Check tetanus status and update immunization and antibiotics as necessary.
  • Determine rabies immune status of the biting animal. In many instances, determination of the nature of the interaction may be critical; determine whether the attack was provoked.
  • If the domestic animal (eg, cat, dog, ferret) is known and can be observed for 10 days, prophylaxis can be postponed. Similarly, prophylaxis can be postponed if a wild animal is caught and is tested for rabies in a timely fashion. If the animal was not captured, proceed with prophylactic immunization.
  • Recommendations for postexposure prophylaxis have changed regarding bat exposure. If rabies cannot be ruled out by testing the bat, consider prophylaxis for any person who had direct contact with a bat, any person who was sleeping who awakened to find a bat near, or any person who may be unaware of contact with a bat.⁵
• Preexposure prophylaxis involves the following:
• • Certain occupations or travel destinations pose a risk for possible rabies exposure. Administer preexposure rabies vaccine to all rabies laboratory workers, animal control officers, veterinarians, spelunkers, and travelers to areas where rabies is enzootic and where immediate access to medical care may not be available.
  • The IM preparations are administered as a 1-mL dose in the deltoid on days 0, 7, and 21 or 28.
  • Vaccine preparations for intradermal administration are no longer recommended or available.²⁰

Surgical Care

• Appropriate wound debridement must be performed, with copious wash out. 
• Antibiotic prophylaxis should be considered.^{17, 21}

Consultations

• Consultation with infectious disease specialists, neurologists, and neurosurgeons may be necessary to assist in diagnosis and management of patients with rabies or patients exposed to rabies.
• Consultation with public health authorities is appropriate to assist in management of bite wound prophylaxis and animal epidemiology.²²
• Also, consult with animal control officers and veterinarians for the management, disposal, and testing of animals that have attacked and injured a human.

MEDICATION

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Mainstays of therapy include the rabies vaccine and human rabies immune globulin (HRIG). Equine-derived rabies immunoglobulin may be the only immunoglobulin available outside of the United States. Vaccine and other biological product shortages can be found at the US Food and Drug Administration (FDA) Web site. 

Drug Category: Immunoprophylaxis agents

Rabies vaccines are produced in tissue culture cell lines and are inactivated.

Human rabies immunoglobulin is produced from individuals who have been vaccinated.

Equine rabies immunoglobulin is produced from immunized horses. Previously, the equine variety had a high reactogenicity rate with serum sickness reactions. Modern production includes more purification steps, and serum sickness reaction rates have been reduced to 1-2% of recipients. For countries other than the United States, equine immunoglobulin is more widely available and cheaper. Recently, shortages of all immunoglobulin products around the world have been a problem.

FOLLOW-UP

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Further Inpatient Care

• Inpatient care of patients with rabies may be needed if wounds are extensive or are on the face and hands, if surgical repair or replacement of blood loss is required, or if infection occurs.

Further Outpatient Care

• Watch for local wound complications and ensure follow-up for the repeated injections of vaccine. Analgesics may be needed for any patient with animal bites.

Transfer

• For a patient with an illness consistent with rabies, transfer to a tertiary care center with intensive care support and capability of providing timely diagnostic workup is essential.

Deterrence/Prevention

• Domestic animal vaccination programs have effectively limited canine rabies in the United States. Encourage families to keep their pet vaccinations up to date and to limit the reproduction of domestic animals to prevent stray populations.⁹
• Massachusetts, Texas, and various countries in Europe have active oral recombinant rabies vaccine drop programs to immunize wildlife to limit geographic spread of terrestrial rabies. Oral vaccines are loaded into feed pellets, which wildlife ingest, and periodic sera checks on animals show effective antibody responses.¹¹

Complications

• Muscle fasciculations, priapism, and focal or generalized convulsions are observed.
• Patients may die immediately or may progress to paralysis, which may be present only in the bitten limb at first but usually becomes diffuse.
• Paralysis may ascend (similar to Guillain-Barré syndrome).
• Coma may last for hours to months with active intensive care support.
• Cardiac arrhythmias, myocarditis, and further autonomic dysfunction lead to cardiopulmonary arrest.

Prognosis

• Rabies is almost always a fatal illness once symptoms begin.
• For cases in which prompt and correct postexposure treatment is administered, no documented failures are reported, and patients do not develop rabies.

Patient Education

• Promote educational efforts at home and at schools teaching children about safety procedures and precautions regarding pets and wild animals. Many communities have programs through camps, schools, and public libraries as well as information through local health department Web sites.²³
• Teach children at an early age not to handle stray animals or wildlife.
• Report any animals that are sick or acting strange to local authorities.
• Keep pets indoors at night and fenced in or on a leash when outdoors.
• Keep pet food and water dishes indoors.
• Remove bat colonies from homes and barns.
• Handle sick or dead animals with heavy gloves and shovels.
• Keep trash container lids tight and maintain compost piles away from dwellings.
• Veterinarians and public health officials are excellent resources for concerns regarding animal rabies prevention.^{9, 24}
• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Rabies.

MISCELLANEOUS

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Medical/Legal Pitfalls

• The most common management errors in reported failures of postexposure prophylaxis are insufficient cleansing of the wounds and improper administration of immunoglobulin.²⁵

Special Concerns

• Children are prone to extensive wounds on the face, upper body, and hands because of their short stature.²⁶ These wounds may require extensive debridement and inpatient management. The dose of human rabies immunoglobulin (HRIG), calculated by body weight, may be of insufficient volume to infiltrate all the wounds. The HRIG may be diluted with sterile saline so that more volume can be used without exceeding the total recommended dose.²⁷
• Pregnancy is not a contraindication to vaccination, although the products used for postexposure prophylaxis are pregnancy category C. Studies have indicated no substantial risk in pregnancy, and, if the risk of exposure to rabies is high, pre-exposure prophylaxis should be considered.^{20, 28, 29, 30}
• Vaccine production problems and higher rates of vaccine use can sometimes lead to shortages of rabies vaccine. Appropriate use of vaccine may be guided by local and state health departments as these issues are resolved.^{31, 20, 22}

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Distribution of the 5 strains of rabies virus and the associated wildlife in the United States.
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

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1. Messenger SL, Smith JS, Rupprecht CE. Emerging epidemiology of bat-associated cryptic cases of rabies in humans in the United States. Clin Infect Dis. Sep 15 2002;35(6):738-47. [Medline].
2. Srinivasan A, Burton EC, Kuehnert MJ, et al. Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med. Mar 17 2005;352(11):1103-11. [Medline]. [Full Text].
3. Centers for Disease Control and Prevention. Investigation of rabies infections in organ donor and transplant recipients--Alabama, Arkansas, Oklahoma, and Texas, 2004. MMWR Morb Mortal Wkly Rep. Jul 9 2004;53(26):586-9. [Medline].
4. Centers for Disease Control and Prevention. Human death associated with bat rabies--California, 2003. MMWR Morb Mortal Wkly Rep. Jan 23 2004;53(2):33-5. [Medline].
5. Pape WJ, Fitzsimmons TD, Hoffman RE. Risk for rabies transmission from encounters with bats, Colorado, 1977- 1996. Emerg Infect Dis. May-Jun 1999;5(3):433-7. [Medline].
6. Blanton J D, Hanlon CA, Rupprecht CE. Rabies surveillance in the United States during 2006. J Am Vet Med Assoc. Aug 15 2007;231(4):540-56. [Medline].
7. Wyatt JD, Barker WH, Bennett NM, Hanlon CA. Human rabies postexposure prophylaxis during a raccoon rabies epizootic in New York, 1993 and 1994. Emerg Infect Dis. May-Jun 1999;5(3):415-23. [Medline].
8. Centers for Disease Control and Prevention (CDC). First human death associated with raccoon rabies--Virginia, 2003. MMWR Morb Mortal Wkly Rep. Nov 14 2003;52(45):1102-3. [Medline].
9. Compendium of animal rabies prevention and control, 2008: National Association of State Public Health Veterinarians, Inc. (NASPHV). MMWR Recomm Rep. Apr 18 2008;57:1-9. [Medline]. [Full Text].
10. Moore DA, Sischo WM, Hunter A, Miles T. Animal bite epidemiology and surveillance for rabies postexposure prophylaxis. J Am Vet Med Assoc. Jul 15/ 2000;217(2):190-4. [Medline].
11. Nel LH, Markotter W. Lyssaviruses. Crit Rev Microbiol. 2007;33(4):301-24. [Medline].
12. Baer GM. The Natural History of Rabies. Boston, MA: CRC Press; 1991.
13. Mrak RE, Young L. Rabies encephalitis in humans: pathology, pathogenesis and pathophysiology. J Neuropath Exp Neurol. 1994;53(1):1-10. [Medline].
14. Tsiang H. Pathophysiology of rabies virus infection of the nervous system. Adv Virus Res. 1993;42:375-412. [Medline].
15. Fisher DJ. Epidemiology and prevention of rabies. Curr Probl Pediatr. Nov-Dec 1995;25(10):304-13. [Medline].
16. Fishbein DB, Robinson LE. Rabies. N Engl J Med. Nov 25 1993;329(22):1632-8. [Medline].
17. Rupprecht CE, Gibbons RV. Clinical practice. Prophylaxis against rabies. N Engl J Med. Dec 16 2004;351(25):2626-35. [Medline].
18. Willoughby RE, Tieves KS, Hoffman GM, et al. Survival after treatment of rabies with induction of coma. N Engl J Med. Jun 16 2005;352(24):2508-14. [Medline]. [Full Text].
19. McDermid RC, Saxinger L, Lee B, et al. Human rabies encephalitis following bat exposure: failure of therapeutic coma. CMAJ. Feb 26 2008;178(5):557-61. [Medline].
20. Manning SE, Rupprecht CE, Fishbein D, et al. Human rabies prevention--United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. May 23 2008;57:1-28. [Medline]. [Full Text].
21. Goldstein EJ. Current concepts on animal bites: bacteriology and therapy. Curr Clin Top Infect Dis. 1999;19:99-111. [Medline].
22. Moran GJ, Talan DA, Mower W, et al. Appropriateness of rabies postexposure prophylaxis treatment for animal exposures. Emergency ID Net Study Group. JAMA. Aug 23-30 2000;284(8):1001-7. [Medline].
23. Dandoy S, Scanlon F. Teaching kids about rabies. Am J Public Health. Mar 1999;89(3):413-4. [Medline].
24. Murray KO, Arguin PM. Decision-based evaluation of recommendations for preexposure rabies vaccination. J Am Vet Med Assoc. Jan 15 2000;216(2):188-91. [Medline].
25. Fescharek R, Schwarz S, Quast U, et al. Postexposure rabies prophylaxis: when the guidelines are not respected. Vaccine. Dec 1991;9(12):868-72. [Medline].
26. Fisher DJ. Resurgence of rabies. A historical perspective on rabies in children. Arch Pediatr Adolesc Med. Mar 1995;149(3):306-12. [Medline].
27. Committee on Infectious Diseases, American Academy of Pediatrics. 2006 Red Book - Report of the Committee on Infectious Diseases. 27. Elk Grove, IL: American Academy of Pediatrics; 2006:552-9.
28. Chutivongse S, Wilde H, Benjavongkulchai M, et al. Postexposure rabies vaccination during pregnancy: effect on 202 women and their infants. Clin Infect Dis. Apr 1995;20(4):818-20. [Medline].
29. Arya SC, Agarwal N. Assessing the safety of post-exposure rabies immunization in pregnancy. Hum Vaccin. Sep-Oct 2007;3(5):155; author reply 155. [Medline].
30. Abazeed ME, Cinti, S. Rabies prophylaxis for pregnant women. Emerg Infect Dis. Dec 2007;13(12):1966-7. [Medline].
31. Wilde H, Tipkong P, Khawplod P. Economic issues in postexposure rabies treatment. J Travel Med. Dec 1999;6(4):238-42. [Medline].

Article Last Updated: Oct 9, 2008