Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find the Rabies Vaccine article more useful, or one of our other health articles.
Treatment of almost all medical conditions has been affected by the COVID-19 pandemic. NICE has issued rapid update guidelines in relation to many of these. This guidance is changing frequently. Please visit https://www.nice.org.uk/covid-19 to see if there is temporary guidance issued by NICE in relation to the management of this condition, which may vary from the information given below.
Rabies is a viral infection affecting the nervous system (peripheral and central), causing encephalitis or meningoencephalitis and almost inevitably death. There are many deaths worldwide every year and prevention of the disease deserves more attention.
Rabies is caused by the rabies virus, genus Lyssavirus and family Rhabdoviridae. The genus Lyssavirus consists of over 80 viruses. There are about 10 viruses in the rabies serogroup, most of which only rarely cause disease in humans. The most common cause of rabies is the genotype 1 virus (classical rabies virus). It is a negative-stranded RNA virus, bullet-shaped with three component parts:
- Surface glycoprotein (G protein).
- Outer envelope (matrix protein).
It is most commonly transmitted in saliva by the bite of an infected mammal. The virus is fragile and inactivated by drying, ultraviolet rays and detergents. The rabies-related lyssaviruses, including European bat lyssaviruses (EBLVs) and Australian bat lyssaviruses (ABLVs), cause rabies much less often. The clinical presentation is indistinguishable from the classical rabies virus.
Pathophysiology[1, 2, 3]
- Any mammal can carry rabies but transmission occurs to humans most commonly worldwide from dogs (over 99% of cases).
- In some countries, bats, monkeys and cats can also transmit rabies. Even in countries which are free of terrestrial rabies, bats may carry a rabies-like virus. (The only case acquired in the UK in the last century was attributed to a bat.) Foxes, racoons and skunks are significant sources in some parts of the world, particularly North America.
- Not all individuals exposed to rabies virus develop the disease but, once symptoms occur, rabies is almost invariably fatal.
- The risk of developing rabies after a bite by a rabid animal varies with the site and severity of the wound.
- Infection does not occur through intact skin. The exposure is usually a bite but can be from exposure of mucous membranes to infected body fluids or neural tissue (although much less likely).
- Infection may occur from droplet (aerosol) spread. This is of concern when venturing into caves inhabited by bats.
- Other than following transplantation, transmission between humans has not been documented.
After inoculation the following ensues:
- The virus enters the peripheral nerves. The virus is highly neurotropic and avoids immune defences by invading neural tissue.
- The virus then incubates for a period of time which reflects size of inoculum and distance to the central nervous system. The incubation period is usually between 3 and 12 weeks but can range from 4 days to 19 years. In 90% of cases incubation is less than 1 year.
- Shorter incubation periods are seen in those with multiple, severe wounds (particularly of the head, which is richly innervated), in children, and when post-exposure treatment fails.
- Amplification occurs until the single-stranded RNA nucleocapsid core spills into myoneural junctions, entering both motor and sensory axons. Prophylactic therapy at this point is futile and the disease advances with a uniformly fatal course.
- The virus spreads in a retrograde manner along axons (at about 1-2 cms per day) and enters spinal ganglions.
- Multiplication of the virus in the ganglions is marked by onset of pain or paraesthesia at the inoculation site. This is a hallmark symptom.
- Spread through the nervous system is now more rapid (at about 30 cms per day) and marked by a progressive encephalitis.
- Finally, the virus spreads peripherally, including to the salivary glands.
- Rabies occurs in all continents of the world except Antarctica, although some countries are rabies-free (including the UK).
- Knowledge exists to eliminate the threat of canine rabies but lack of motivation by governments, cultural issues and lack of funding prevent progress.
- There are estimated to be up to 61,000 deaths from rabies worldwide every year. 95% of these deaths occur in Africa and Asia. Rabies is much more prevalent in developing countries, particularly India, which has the highest number of deaths.
- In the UK, deaths from classical rabies continue to occur in people infected abroad. However, it is rare with only 25 deaths since 1946. No indigenous cases have been reported in the UK other than from bats since 1902, and only one of these has been reported.
- In the UK, rabies-related viruses have been detected in Daubenton's bats but not in the most common species of bats. Knowledge of prevalence and epidemiology in the bat population is limited; however, the possibility of exposure is significant and has implications for preventative measures.
- Children are particularly at risk, as they are more likely to approach animals without caution. 40% of the deaths worldwide occur in children under the age of 15.
- A dramatic fall occurred in fox-adapted rabies in Western Europe at the end of the 20th century with vaccination of wild and domestic animals.
- The illness has an insidious onset. Patients may not recall the exposure because the incubation period can be so long.
- Early symptoms include pain and paraesthesia around the wound or inoculation site, malaise, fever and headache. There may be weakness of the bitten limb.
- There may be itching at the site of the wound, which spreads towards the face.
- Early symptoms progress rapidly to the neurological phase, with coma and death following within two weeks of neurological symptoms.
- Neurological symptoms include hydrophobia, hallucinations and behavioural disturbance (for example, mania).
- It then progresses to an ascending flaccid paralysis with sensory disturbances and coma.
- Death results from respiratory paralysis. Once clinical symptoms develop, no specific treatment will prevent death and supportive treatment only can be given.
Stages of the disease
The stages of the disease in clinical context are:
- No symptoms.
- Virus transfers from periphery to CNS.
- Variable duration (usually between 3 and 12 weeks but up to 19 years).
- No antibody response detectable.
- Virus enters CNS.
- Duration 2 to 10 days.
- Pain or paraesthesia at the inoculation site. May be associated with weakness in the affected limb.
- Nonspecific symptoms of systemic viral disease:
Acute neurological stage
- Duration 2-7 days.
- Different forms:
- 'Furious rabies', the more common form, (two thirds of cases) with:
- The onset marked by increasing insomnia, periods of extreme agitation, delirium and hyperactivity.
- Episodes which may be accompanied by frothing at the mouth, difficulty swallowing, vomiting and intense spasms affecting the muscles of deglutition and the accessory muscles of respiration.
- Hydrophobia, which is precipitated by attempts to drink or by the sight, sound or mention of water or other fluids.
- Accompanying features, which may include nuchal rigidity, photophobia, fasciculations, cerebellar signs, cranial nerve palsies, dysphasia, hypertonia or hypotonia, extensor plantar responses and convulsions.
- Deterioration, which is marked by evolution of flaccid paralysis, coma and irregular respiration.
- Untreated individuals survive for 2-12 days once symptoms develop.
- Paralytic, 'dumb' or 'apathetic' rabies (around 30%):
- 'Furious rabies', the more common form, (two thirds of cases) with:
- Fasciculations and piloerection.
- Ascending paralysis or symmetric quadriparesis.
- More likely to pose diagnostic difficulties because spasms and hydrophobia seldom appear.
- The paralysis begins in the bitten limb in many cases, spreads rapidly and symmetrically and may be misdiagnosed as Guillain-Barré syndrome. (Distinguishable from this by fever, intact sensation other than at site of bite, bladder dysfunction and myoedema.)
- Involvement of the muscles of deglutition, articulation and respiration generally occurs terminally.
- The average survival is 7-12 days.
Assessment of the suspect animal
It may be appropriate for suspect animals to be observed in quarantine for 15 days. The contact animal in some cases may be available to be examined. The brain tissue in such cases (often bats) or when the animal is symptomatic is examined. Bats may transmit rabies without an obvious history of biting.
Investigation in humans[5, 6]
Ante-mortem diagnosis has been traditionally challenging, although newer diagnostic assays give a higher possibility of rapid results. Traditionally, antibody assays, antigen detection and virus isolation have met with limited success. Particularly in paralytic rabies, where the diagnosis is less clear clinically, improved diagnostics are vital.
- Confirmation of rabies relies on isolation of virus, presence of virus antigens, presence of rising numbers of virus-specific antibodies in serum or CSF, or the presence of viral nucleic acids detected by molecular methods in samples from skin, brain, saliva or concentrated urine.
- Nuchal skin biopsy is increasingly used, with samples taken from the hairline at the base of the neck and subjected to fluorescent antibody testing. Viral antigen is found in the nerve fibres surrounding the base of hair follicles.
- Post-mortem, rabies virus antigen is found in infected tissues, usually a brain smear or biopsy, by the fluorescent antibody test.
- A number of newer molecular diagnostic assays have been developed and investigated and show promise for the future.
- Imaging is not usually helpful. CT scans are normal; MRI scan may show non-enhancing, ill-defined, mild hyperintensity changes. Electroencephalograph (EEG) usually shows diffuse slow wave activity or an isoelectric recording.
Management[2, 3, 7]
- Preventative therapy for rabies, including wound cleansing and active and passive immunisation after a recognised exposure, is highly efficacious. Post-exposure prophylaxis is nearly 100% effective at preventing rabies.
- Without prophylaxis before the onset of prodromal symptoms, death is almost certain.
- There have been several survivors from rabies and all but one received rabies vaccine prior to the onset of clinical illness.
- Clean the wound, using soap or detergent, under running tap water for several minutes. Then treat with a suitable disinfectant (eg, 40-70% alcohol, povidone iodine).
- Primary suturing of the wound should be avoided or postponed.
- Human rabies-specific immunoglobulin (HRIG) can be infiltrated into the wound.
- Remember anti-tetanus prophylaxis.
In the UK a Public Health England (PHE) risk assessment form should be completed. Information gathering will be required, including the name and address of the animal's owner where relevant to allow follow-up. This may require enlistment of help from local officials. This assessment then informs a level of risk, which then guides the management protocol/guidelines. The risk assessment form then acts as a prescription if immunoglobulin or vaccine is required. It comprises the following elements:
- Personal details: name, age, date of birth, address, medical history.
- Date of exposure: because of the wide variation in incubation, there is no time limit to giving treatment, although rabies immunoglobulin is not usually required if exposure was over a year ago.
- Animal involved: species and current state of health. It is important to determine the vaccination status of the animal where possible. For domestic animals, if the animal can be observed and remains well and behaves normally 15 days after the date of an exposure it will not have had rabies infection at the time of exposure. Decisions about the need for post-exposure treatment within the 15 days will depend on other risk factor assessment.
- Country of exposure: certain countries are known to be free of terrestrial rabies; however, all countries may be considered high-risk where bats are implicated. Relative risk by country is available on the PHE website, as well as the National Travel Health Network and Centre (NaTHNaC) website.
- Type and site of exposure. Bites are higher risk than scratches; head and neck injuries are higher risk than distal injuries.
- Previous rabies vaccination history.
This is by the use of rabies vaccine. In non-immunised individuals, human rabies-specific immunoglobulin (HRIG) is also given, which provides immunity whilst waiting for the antibody response. Globally, the schedule and the vaccines used differ. The following is a summary of the full algorithm which is available on the PHE website, which also contains the logistics of obtaining HRIG and vaccines, and advice on finishing post-exposure treatment courses which were initiated abroad.
Rabies exposure risk
Unimmunised or not completely immunised
|None||No immunisation||No further immunisation|
|Low||5 doses rabies vaccine on days 0, 3, 7, 14 and 28-30||2 doses on days 0 and 3-7|
|High||5 doses rabies vaccine on days 0, 3, 7, 14 and 28-30|
PLUS HRIG on day 0 only
|2 doses on days 0 and 3-7|
Management after development of symptoms
- Symptomatic rabies is almost invariably fatal and the treatment aims to alleviate suffering and support vital functions.
- Patients are usually managed in the ITU setting as appropriate.
- Some intensive care strategies have been proposed following occasional rabies survival cases but remain controversial.
- At present, there is no specific treatment of rabies. Antiviral treatments to date have not been successful.
- Extra barrier precautions are not required, as transmission requires a break in the skin. Hospital staff and contacts do not require post-exposure treatment unless they have been bitten, or if infected saliva, CSF or brain tissue has come into contact with their mucous membranes or open wounds.
July 2018 - Dr Hayley Willacy draws your attention to the recently released PHE guidelines on post-exposure prophylaxis - see Further reading below. Changes have been made to definitions of exposures and animal/country risk, recommended number of vaccine doses for immunocompetent individuals, recommendations on the use of human rabies immunoglobulin (HRIG) and on the management of immunosuppressed individuals.
The category should be combined with information on country/animal risk stratification to determine the composite rabies risk. Low exposure category (Category 3) with low or high country/animal risk has a green composite risk. Category 2 and 3 exposures with low risk and category 2 exposure with high risk are classified as amber. Category 3 exposure with high country/animal risk has a red composite risk.
For green risk, no post-exposure treatment is required. Patients in the amber risk grouping should receive four doses of vaccine on day 0 (d0), d3, d7 and d21 if non-/partially immunised. Two doses of vaccine on d0 and d3-7 are recommended for fully immunised patients. For immunosuppressed individuals, HRIG and five doses of vaccine on d0, d3, d7, d14 and d30 are advised. For patients who fall into the red category of composite risk, the recommendations are HRIG and four doses of vaccine on d0, d3, d7 and d21 for those who are non-/partially immunised. In fully immunised and immunosuppressed individuals, recommended post-exposure treatment is two doses of vaccine on d0 and d3-7 and HRIG with five doses of vaccines on d0, d3, d7, d14 and d30. The guidelines state that HRIG is not required if more than seven days have elapsed since the first dose of vaccine, or more than one day has elapsed since the second dose or for partially immunised patients unless immunosuppressed.
It is essential to administer post-exposure prophylaxis correctly. Death is almost certain if early treatment fails to prevent progression to infection and prodromal symptoms.
Only a handful of cases of survival of human rabies have been documented, mostly in people who had either been previously vaccinated or who had received post-exposure prophylaxis.
The way forward for reducing deaths from rabies worldwide is with prevention. Elimination of rabies in the reservoir animal species is considered a cost-effective strategy and achievable even in low-income countries; however, it requires a collaborative approach to vaccinate domestic animals, and control strays. This involves governments and human and animal health authorities, as well as diagnostic and surveillance teams. With the post-exposure preventative regimes, it has been estimated that rabies can be prevented in around 327,000 people annually. Risk is further reduced by vaccination of people in high-risk areas or occupations and of travellers visiting endemic areas.
Reduction of risk
- Avoidance of contact with potentially rabid animals.
- Control of rabies in the animal population:
- Vaccination of domestic dogs, cats and ferrets.
- Euthanasia of unvaccinated pets in contact with a rabid animal (or six months' isolation, and vaccination one month prior to release).
- The Pet Travel Scheme has replaced quarantine in the UK. This is a vaccination-based programme. Animals entering the UK have to have proof of rabies vaccination and subsequent immunity.
- Vaccination and control of certain wild animals:
- Control and localised oral vaccination of foxes.
- Animal control and vaccination strategies have proved successful in preventing spread of rabies in a number of countries.
Immunisation of at-risk groups
- Laboratory workers handling the virus.
- Workers handling imported animals.
- All handlers of bat species.
- Workers in at-risk jobs, in at-risk areas (for example, zoo workers, veterinary staff, local authority animal inspectors).
- Health workers likely to have contact with body fluids or tissue from infected patients.
- Travellers to endemic areas where work involves handling animals.
- Travellers to endemic areas, who may be more than 24 hours from modern medical treatment.
- Active vaccination - post-exposure vaccination.
- Passive immunisation - HRIG, used at the start of all primary post-exposure courses of rabies vaccine.
See the separate Rabies Vaccination article for further details.
- This fearful disease dates back as far as the association between man and dogs.
- There is a possible reference as long ago as the 23rd century BC in Babylon, which describes the disease in dogs and the lethal effect in man if bitten.
- The term hydrophobia was first used in a Roman description from the 1st century AD.
- In the 16th century, Spanish soldiers were described as showing signs of madness after bites from vampire bats.
Further reading and references
Finke S, Conzelmann KK; Replication strategies of rabies virus. Virus Res. 2005 Aug111(2):120-31.
Briggs DJ; The role of vaccination in rabies prevention. Curr Opin Virol. 2012 Apr 11.
Guidelines on managing rabies post-exposure; Public Health England (June 2018)
Dietzschold B, Li J, Faber M, et al; Concepts in the pathogenesis of rabies. Future Virol. 2008 Sep3(5):481-490.
Crowcroft NS, Thampi N; The prevention and management of rabies. BMJ. 2015 Jan 14350:g7827. doi: 10.1136/bmj.g7827.
Rabies: the green book, chapter 27; Public Health England (April 2013)
Rabies; World Health Organization
Mani RS, Madhusudana SN; Laboratory diagnosis of human rabies: recent advances. ScientificWorldJournal. 2013 Nov 142013:569712. doi: 10.1155/2013/569712.
Madhusudana SN, Sukumaran SM; Antemortem diagnosis and prevention of human rabies. Ann Indian Acad Neurol. 2008 Jan11(1):3-12. doi: 10.4103/0972-2327.40219.
Rabies: risk assessment, post-exposure treatment, management; Public Health England
Request Form for Rabies Post-exposure Treatment; Public Health England
Yousaf MZ, Qasim M, Zia S, et al; Rabies molecular virology, diagnosis, prevention and treatment. Virol J. 2012 Feb 219:50.
Taking your pet abroad; GOV.UK