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Last Update: October 31, 2022.

Continuing Education Activity

Rabies causes viral encephalitis which kills up to 70000 people/year worldwide. Infected animal saliva transmits viral encephalitis to humans. Rabies is one of the oldest known diseases in history with cases dating back to 4000 years ago. For most of human history, a bite from a rabid animal was uniformly fatal. In the past, people were so scared of rabies that after being bitten by a potentially rabid animal, many would commit suicide. This activity describes the pathophysiology of rabies and stresses the importance of an interprofessional team in its management.


  • Identify the etiology of rabies.
  • Review the pathophysiology of rabies.
  • Outline the treatment and management options available for rabies.
  • Describe interprofessional team strategies for improving care and outcomes in patients with rabies.
Access free multiple choice questions on this topic.


Rabies causes viral encephalitis which kills up to 70,000 people/year worldwide. Infected animal saliva transmits viral encephalitis to humans. Rabies is one of the oldest known diseases in history with cases dating back to 4000 years ago. For most of human history, a bite from a rabid animal was uniformly fatal. In the past, people were so scared of rabies that after being bitten by a potentially rabid animal, many would commit suicide. Pasteur's rabies vaccine from 1885 has led to such intense prophylaxis in developed countries, that in the United States, for example, there have only been about two rabies deaths per year for the past two decades; less developed countries are not so lucky.[1][2][3]


The Rhabdoviridae family of viruses that are bullet-shaped and composed of two parts cause rabies. The first part is considered more structural and is a viral envelope while the second part is more functional and contains the ribonucleocapsid core. The virus is most commonly spread through the bite of an infected mammal, including domestic and wild ones, but transmission can occur from saliva through broken skin or mucous membranes. Other routes of infection include inhalation of the virus in an aerosolized form, ingestion, transplacentally, and even through organ transplants.[4][5]


Researchers estimate that 30,000 to  70,000 deaths are attributable to rabies each year, with less developed countries affected more. In the United States, there are few human cases reported, though that may be due to the widespread use of post-exposure prophylaxis and the prevention programs in place. In developed countries, domesticated animals have only been responsible for about 10% of cases of rabies transmission, while wild animals such as skunks, raccoons, foxes, and especially bats are responsible for the rest of the cases. Any mammal may carry rabies, and so while small rodents and the rabbit family usually are considered safe as they are not expected to survive an inoculating wound from a rabid animal, there have been anecdotal reports of rabies caused by transmission from rats. As animal carriers vary by region, it is important to know your region’s carriers to help determine who may need prophylaxis.[6][7]


Following viral transmission, the rhabdovirus travels through the peripheral nervous system targeting the central nerves, which then leads to encephalomyelitis. In humans, the first symptoms seem like any other nonspecific viral syndrome (fever, malaise, headache). These benign symptoms may then progress to anxiety, then to agitation, and then to frank delirium. One very consistent symptom after a rabid bite is tingling at the bite site within the first few days. Interestingly enough, after the virus has spread from peripheral nerves to the central nervous system (CNS), it then travels back to the peripheral nervous system, particularly affecting highly innervated areas (e.g., salivary glands). The "frothing" as portrayed in the movies Cujo and Old Yeller, is due to hypersalivation, and victims can suffer from intense pharyngeal muscle spasm at the mere sight, taste, or sound of water. This is called "hydrophobia." Eventually, the virus progresses to complete failure of the entire nervous system which causes a quick death. While animals tend to die within ten days, the incubation period following inoculation can last two weeks to six years, averaging a few months. Determining factors for the time of onset include the viral load, location of exposure, and severity of the wound. The virus ultimately affects the central nervous system, usually affecting the brainstem more severely. The toxic effects occur through an inflammatory response, with functional changes not completely understood. Ultimately the virus is suspected to affect neurotransmission, and apoptosis may occur through virus-dependent and cell-dependent routes. Once clinical features are seen, rabies is universally fatal.[8]


Autopsy studies have revealed that the brain usually is swollen, congested, and has an acute inflammatory process. In most cases, the presence of neuronal death is rare. Immunochemical staining will reveal deposits of the virion in the nerve cytoplasm. Negri bodies are often seen on light microscopy but only in about two-thirds of cases.

History and Physical

The history of a rabies-infected patient may be simple and straightforward with a known bite from a rabid animal. Unfortunately, it may be challenging to obtain a history pointing towards rabies due to the potential for a long incubation period and multiple potential transmission methods.

There are five stages of rabies following inoculation: incubation; prodrome; acute neurologic illness; coma; and death.  

Incubation is the period defined as an inoculation to the first onset of symptoms and can range from days to years.

The prodrome phase includes nonspecific symptoms similar to flu-like illnesses with gastrointestinal symptoms, myalgias, and fevers being some of the possible symptoms.

The third stage of rabies is when neurologic symptoms occur. These are classified into one of three categories: encephalitic (also considered "furious"), paralytic (also considered "dumb"), and a rare non-classic form.

  • The encephalitic form is most common and presents in approximately 85% of cases. These patients may exhibit hydrophobia or aerophobia, which is when spasms develop as a result of stimuli such as swallowing liquids (hydrophobia).  Agitation and changes in mentation can occur during the encephalitic form, with the potential for autonomic dysfunction, increased deep tendon reflexes, nuchal rigidity, and finding positive Babinski sign. Other examination findings outside the nervous system can include tachycardia, tachypnea, and fever.   This progresses rapidly to hyperactivity.
  • The paralytic form of rabies is less common and noted to occur less than 20% of the time. These patients may be confused with Guillain-Barre syndrome as the classically associated hydrophobia, and irritability is not seen. Weakness is a hallmark, though patients may also have altered mentation, ongoing fevers, and bladder dysfunction.
  • The final form of rabies is considered non-classic and is rare, generally associated with seizures and more profound motor and sensory symptoms.

Stage 4 of rabies is the coma stage and usually begins within ten days of stage 3. Patients may have ongoing hydrophobia, develop prolonged apnea periods, and have flaccid paralysis.

Following the onset of stage 4, without supportive care due to cardiopulmonary failure, most patients experience death within two to three days. Even with supportive therapy, virtually zero patients survive rabies.


Without a clear-cut rabid bite history, rabies is often a diagnosis of exclusion. In early stages, it may manifest similar to influenza, Coxsackie, enterovirus, and herpes. In later stages, rabies may present similarly to delirium tremens, tetanus, botulism, diphtheria, tick-borne diseases, and Guillain Barre. It is common for physicians to check CBC, electrolytes, cultures, CT, chest x-ray, and MRI and still, have no idea that rabies is the culprit. Unless isolated in a rabies-specific viral culture, detected by polymerase chain reaction (PCR) in saliva, found to have positive antibody titer, or isolated in cerebrospinal fluid (CSF), the diagnosis may continue to be elusive until too late.

Rabies can be diagnosed through multiple routes using CSF, blood, saliva, tears, and tissue biopsies (neck, immunofluorescent stain). CSF analysis can show a pleocytosis and may allow isolation of the virus.  The Centers for Disease Control and Prevention notes that no single test is enough to rule in or out rabies.  Ultimately, a high level of suspicion is required in developed countries due to the rarity of the disease.[9][10][11]

If the biting animal can be euthanized and tested then that may prevent the need to administer post-exposure prophylaxis. Public health may be able to facilitate the testing of the animal.

Treatment / Management

There is no effective treatment for rabies. Prevention is the mainstay of treatment including programs involving domestic animal vaccination, education, and monitoring.[12][13][14]

Wound care is the first step in the treatment of any individual with a feared rabies exposure. Appropriate wound care alone has been noted to be almost 100% effective if initiated within three hours of inoculation. Recommendations include scrubbing the wound and surrounding area with soap and water (solutions include 20% soap solution, povidone, and alcohol solutions), and swabbing deeply for puncture wounds, with irrigation. After cleaning the wound thoroughly the application of a virucidal agent such as benzalkonium chloride or povidone-iodine is recommended.

In the United States, when a bite is known to be from a bat, skunk, raccoon, or fox, treat immediately with rabies vaccine and rabies immune globulin. For all other bites, consult the public health department. Outside of the United States, a dog bite should be treated immediately with vaccine and rabies immune globulin.

Treatment is then initiated based on if the patient was previously immunized or not. For patients with previous immunization, a typical treatment may be with a human diploid cell vaccine or purified chick embryo cell vaccine at a dose of 1 mL injected intramuscularly on the day it occurs (day 0) and on day 3.

If the patient has not been previously immunized, the treatment still involves dosing with one of the two vaccines listed above with 1 mL given intramuscularly on days 0, 3, 7, and 14 (and on day 28 if the individual is immunosuppressed). The dose of the vaccine should be given at a site distant from where the second part of treatment (human rabies immune globulin or HRIG) is given. These unimmunized patients are treated with human rabies immune globulin as well at a dose of 20 IU/kg, with a preference to infiltrate as much of that dose around the wound as possible. Any remaining dose of human rabies immune globulin not infiltrated into the wound is then given intramuscularly, and as mentioned above is given at a site distant from the vaccine.

Recently, recommendations have been updated in the United States, and since bats are by far the major source of rabies here, any person who awakens from sleep and finds a bat in the room should be urgently immunized.

Differential Diagnosis

  • Psychosis
  • Seizures
  • Poisoning with belladonna alkaloids
  • Stroke
  • Jacob Creutzfeldt disease
  • Brain tumor
  • Encephalitis
  • Tetanus


  • Seizures
  • Fasciculations
  • Psychosis
  • Aphasia
  • Autonomic instability
  • Paralysis
  • Coma
  • Death


  • Neurologist
  • Infectious disease
  • Neurosurgeon
  • Public health

Enhancing Healthcare Team Outcomes

When a diagnosis of rabies is made, an interprofessional team is necessary as the repercussions of this infection go way beyond the acute infection.

Blood transfusions have not been documented to transmit rabies, though it has been suggested to hold donation for one year following exposure prophylaxis. If no exposure was noted, but vaccination occurred there is a recommendation to wait four weeks.

Since rabies is entrenched within the native animal population in the United States, there will continue to be human exposure to this fatal disease. Public health officials take a very active role in preventing rabies, both before exposures as well as after possible exposures.

Animal control has to be notified to determine if the domestic animals require vaccination. In addition, vaccination of workers who may be exposed to rabies may also be necessary.

Patients need to be educated on avoiding contact with wildlife, and if ever bitten, the area should be thoroughly washed to lower the risk of rabies transmission. All dead and sick animals should be handled with heavy gloves. If bitten by a wild animal, one should seek immediate medical assistance. [15][16][17](Level V)


For those who develop symptoms of rabies, survival is rare. Only a handful of survivors exist in the USA after acquiring rabies. For those without symptoms but with rabies vaccine prophylaxis, survival is assured. Individuals who are bitten by a rabid animal need the rabies vaccine and immunoglobulin ASAP for survival- once the symptoms appear, death is inevitable.[18][19] [Level 5]

Review Questions


Bedeković T, Lohman Janković I, Šimić I, Krešić N, Lojkić I, Sučec I, Robardet E, Cliquet F. Control and elimination of rabies in Croatia. PLoS One. 2018;13(9):e0204115. [PMC free article: PMC6147469] [PubMed: 30235274]
Pedersen K, Schmit BS, DeLiberto TJ, Suckow JR, Davis AJ, Slate D, Chipman RB, Hale RL, Gilbert AT. Raccoon (Procyon lotor) biomarker and rabies antibody response to varying oral rabies vaccine bait densities in northwestern Pennsylvania. Heliyon. 2018 Sep;4(9):e00754. [PMC free article: PMC6129686] [PubMed: 30211329]
Sambo M, Hampson K, Changalucha J, Cleaveland S, Lembo T, Lushasi K, Mbunda E, Mtema Z, Sikana L, Johnson PCD. Estimating the Size of Dog Populations in Tanzania to Inform Rabies Control. Vet Sci. 2018 Sep 07;5(3) [PMC free article: PMC6164483] [PubMed: 30205470]
Yang DK, Kim HH, Cho IS. Strategies to maintain Korea's animal rabies non-occurrence status. Clin Exp Vaccine Res. 2018 Jul;7(2):87-92. [PMC free article: PMC6082677] [PubMed: 30112347]
Lu XX, Zhu WY, Wu GZ. Rabies virus transmission via solid organs or tissue allotransplantation. Infect Dis Poverty. 2018 Aug 15;7(1):82. [PMC free article: PMC6092857] [PubMed: 30107857]
Yahiaoui F, Kardjadj M, Laidoudi Y, Medkour H, Ben-Mahdi MH. The epidemiology of dog rabies in Algeria: Retrospective national study of dog rabies cases, determination of vaccination coverage and immune response evaluation of three commercial used vaccines. Prev Vet Med. 2018 Oct 01;158:65-70. [PubMed: 30220397]
Broban A, Tejiokem MC, Tiembré I, Druelles S, L'Azou M. Bolstering human rabies surveillance in Africa is crucial to eliminating canine-mediated rabies. PLoS Negl Trop Dis. 2018 Sep;12(9):e0006367. [PMC free article: PMC6126826] [PubMed: 30188896]
Ugolini G, Hemachudha T. Rabies: changing prophylaxis and new insights in pathophysiology. Curr Opin Infect Dis. 2018 Feb;31(1):93-101. [PubMed: 29293476]
Hennenfent AK, Iyengar P, Davies-Cole J. Assessing rabies knowledge gaps in human and animal healthcare professionals practicing in Washington, DC-A one health approach. Zoonoses Public Health. 2018 Dec;65(8):947-956. [PubMed: 30099849]
Amparo ACB, Jayme SI, Roces MCR, Quizon MCL, Mercado MLL, Dela Cruz MPZ, Licuan DA, Villalon EES, Baquilod MS, Hernandez LM, Taylor LH, Nel LH. The evaluation of Animal Bite Treatment Centers in the Philippines from a patient perspective. PLoS One. 2018;13(7):e0200873. [PMC free article: PMC6062032] [PubMed: 30048466]
Robardet E, Rieder J, Barrat J, Cliquet F. Reconsidering Oral Rabies Vaccine Bait Uptake Evaluation at Population Level: A Simple, Noninvasive, and Ethical Method by Fecal Survey Using a Physical Biomarker. J Wildl Dis. 2019 Jan;55(1):200-205. [PubMed: 30016214]
Langedijk AC, De Pijper CA, Spijker R, Holman R, Grobusch MP, Stijnis C. Rabies Antibody Response After Booster Immunization: A Systematic Review and Meta-analysis. Clin Infect Dis. 2018 Nov 28;67(12):1932-1947. [PubMed: 29788204]
Middleton D, Edwin JJ, Johnson KO, Warshawsky BF. A descriptive analysis of rabies post-exposure prophylaxis data: 2013, Ontario, Canada. Zoonoses Public Health. 2018 Feb;65(1):e66-e78. [PubMed: 29027355]
Lampejo T, Bruce M, Teall A, Dall'Antonia M, Crawley-Boevey E, Grant P, Polhill S, Pillay D, Brown D, Brown M, Nastouli E. Caring for a patient with rabies: implications of the Milwaukee protocol for infection control and public health measures. J Hosp Infect. 2017 Aug;96(4):385-391. [PubMed: 28559126]
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Prevaldi C, Paolillo C, Locatelli C, Ricci G, Catena F, Ansaloni L, Cervellin G. Management of traumatic wounds in the Emergency Department: position paper from the Academy of Emergency Medicine and Care (AcEMC) and the World Society of Emergency Surgery (WSES). World J Emerg Surg. 2016;11:30. [PMC free article: PMC4912791] [PubMed: 27330546]
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Disclosure: Ron Koury declares no relevant financial relationships with ineligible companies.

Disclosure: Steven Warrington declares no relevant financial relationships with ineligible companies.

Copyright © 2024, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK448076PMID: 28846292


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