Virology

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 an RNA virus, bullet-shaped with 3 component parts:

• Surface glycoprotein (G protein)
• Outer envelope (Matrix protein)
• Nucleocapsid

It is 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 - European bat lyssaviruses (EBLVs) and Australian bat lyssaviruses (ABLVs) cause rabies much less often.² The clinical presentation is indistinguishable from the classical rabies virus.³

Pathophysiology

Any mammal can carry rabies but transmission occurs to humans most commonly worldwide from dogs and bats. Human rabies reflects both the extent of the animal reservoir of infection and the contact humans have with animals in this reservoir. Infection has been detected in a wide range of animals worldwide (from racoons and skunks to cats and cattle). In some parts of the world cats and monkeys are important sources of exposure. In Europe and the UK EBLV-1 and EBLV-2 (in bats) have occasionally caused human disease.³ After inoculation the following ensues:

• 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 does not occur through intact skin.
• Infection may occur from droplet (aerosol) spread. This is of concern when venturing into caves inhabited by bats.
• 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 be as long as 19 years.³ In 90% of cases incubation is less than 1 year.
• 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 along axons (at about 1 to 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.

Epidemiology

• Rabies occurs in all continents of the world except Antarctica, although some countries are rabies-free.³ Knowledge exists to eliminate the threat of canine rabies but lack of motivation by governments, cultural issues and lack of funding prevent progress.¹ This is surprising when the number of deaths from rabies worldwide is greater than that from poliomyelitis, meningococcal meningitis, Japanese encephalitis, yellow fever, severe acute respiratory syndrome (SARS) and other diseases which attract more attention.¹ There are estimated to be around 55,000 deaths from rabies worldwide every year.⁴
• The UK, like Australia, although rabies-free, both have rabies-related viruses in their bat populations. 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, but the possibility of exposure is significant and has implications for preventative measures.^2,5
• Rabies is much more prevalent in developing countries, particularly India. Control of disease in developing countries is difficult.⁶ There is wide under-reporting but the World Health Organization (WHO) estimates 35,000 to 50,000 deaths worldwide every year from rabies. About 10 million people around the world receive post-exposure prophylaxis annually.
• Historically there were more human deaths from rabies in the early 20th century (about 50 per year in the USA). Deaths from rabies have been dramatically reduced in the USA by a canine rabies vaccination programme introduced in 1940 (now only on average 2 deaths from rabies every year).
• 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. Rabies remains prevalent in foxes and domestic animals in Eastern Europe and Turkey.³
• In the UK deaths from classical rabies continue to occur in people infected abroad. However it is rare with only 24 deaths since 1902. In 2000 295 people received prophylaxis in England and Wales on return to the UK after exposure abroad.
• In 2002 a man died in the UK from EBLV-2 acquired from a bat in the UK.³ Only 3 similar such cases across Europe have been reported in the last 30 years.^2,3,5
• Rabies appears to be an increasing problem in China.⁷
• Animals involved in human transmission include:
  • Dogs and cats (90% of cases worldwide)
  • Bats (main vector in the USA with 30 of 39 bat species reported rabid at some time)
  • Foxes
  • Racoons (significant in some USA eastern coastal states since the 1950s)⁸
  • Skunks (central USA and California)
• Other possible, but very rare, causes of transmission:
  • Contact with unpasteurised milk. In the USA about 150 rabid cattle have been reported to the Centers for Disease Control (CDC).
  • Transplanted tissue:⁹
    • Corneal transplants.
    • Kidney and liver transplants. Rare reported cases of rabies after transplantation from an infected donor.¹⁰

Presentation

• 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.
• The disease can present with 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.
• 5 cases of survival of human rabies have been documented, all in people who had either been previously vaccinated or who had received post-exposure prophylaxis.

Stages of the disease

The stages of the disease in clinical context are:

• Incubation:
  • No symptoms
  • Virus transfers form periphery to CNS
  • Variable duration (usually between 3 and 12 weeks but up to 19 years)
  • No antibody response detectable
• Prodromal stage:
  • Virus enters CNS
  • Duration 2 to 10 days
  • Nonspecific symptoms:
    • Pain or paraesthesia at the inoculation site is pathognomonic
    • Malaise
    • Fever
    • Anorexia
    • Nausea
    • Insomnia
    • Depression
    • Anxiety and agitation
• Acute neurological stage:
  • Objective and developing CNS disease with symptom pattern (determined by whether the brain or spinal cord is mainly affected)
  • Duration 2-7 days
  • Different forms:
    • 'Furious rabies', the more common form, (80%) with:
      • Initially agitated, confused and hyperactive
      • After hours to days, becomes episodic with calm periods
      • Ends with cardiorespiratory arrest or paralysis
    • Paralytic, 'dumb' or 'apathetic' rabies (20%):
      • Patients may be relatively calm
      • Paralysis occurs early
      • Fever and headache occur prominently
• Coma:
  • Begins within 10 days of onset
  • Duration variable
  • Death occurs quickly without intensive care
  • Even with intensive care, death occurs within 14 days

Differential diagnosis¹¹

Cephalic tetanus, but consider:

• Guillain-Barré syndrome (ascending paralysis similar to dumb rabies)
• Viral encephalitis¹²
• Poliomyelitis
• Transverse myelitis
• Psychosis
• Epilepsy
• Atropine poisoning
• Creutzfeldt-Jacob disease
• Stroke
• Intracranial tumours
• Delirium tremens and some plant toxins and drugs

Investigations

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. When bats are found in the house or bedroom it is recommended that they be caught and tested for rabies as this can avoid the need for rabies immunisation.^11,12

Investigation in humans

Assessment of patients with suspected rabies may involve a number of investigations. The ideal test would detect the virus early with 100% specificity and sensitivity.

Bloods and laboratory studies

• Saliva. Cultures can be detected within 2 weeks of onset of illness.
• Specific testing:
  • Various available but only detection of viral RNA by polymerase chain reaction (PCR) is 100% specific. This is likely to be used more often in the future.
  • Fluorescent antibody testing can be detected early in the illness (in hair follicles of skin biopsy with 67% sensitivity and corneal smears with only 25% sensitivity).
  • Other antibody tests (of serum and cerebrospinal fluid (CSF)) are used but antibodies are not detectable in unvaccinated patients until the second week of illness.
• Blood gases to monitor initial respiratory alkalosis, progressing to respiratory acidosis with respiratory depression.
• CSF examination:
  • No specific features.
  • 80% show monocytosis after 7 days of illness.
• Haematology:
  • Not that helpful in diagnosis.
  • Often normal.
  • Less than 10% show atypical monocytes.
• New tests and future tests:
  • Urine testing. This may detect the virus by a nucleic acid sequence-based amplification technique (NABSA).
  • NABSA technique on saliva or CSF may be used in the future.

Imaging

Normal MRI and CT scans help exclude other conditions which may cause similar symptoms.

Biopsy

Skin biopsy may be performed. Histologically eosinophilic cytoplasmic inclusions (Negri's bodies) are seen in 70% of cases.

Management^11,13

• Immediate bite/wound management:
  It is important to assess what management is appropriate and the level of risk. Rabies is a fatal disease and prevention of progression to the disease is essential. This is covered in more detail in the separate article Rabies Vaccination and the Green Book.³ Pregnancy is not a contra-indication to post-exposure prophylaxis of rabies.
  • Wound care:
    • Immediate and vigorous wound cleansing.
    • Clean with 1 part soap and 4 parts water.
    • Use viricidal agents if available (for example, povidone-iodine).
    • Remove foreign material from the wound and rinse under running water.
    • In hospital explore, debride and irrigate wounds. Delay suturing of wounds and occlusive dressings where possible.
    • Remember anti-tetanus prophylaxis.
  • Active and passive immunisation.³ Essentially this is given as follows:
    • Passive immunisation with human rabies immunoglobulin where there has been no prior active immunisation.
    • Active immunisation should be given to both those who have not had prior active immunisation and in reduced doses for those who have had previous active immunisation (booster series).
    Note: travellers who have had active immunisation do not need passive immunisation. Important, as human immunoglobulin is often hard to get hold of. More detailed information can be found in the rabies vaccination article.
• Management after development of symptoms:
  Symptomatic rabies is almost invariably fatal and the treatment aims to alleviate suffering and support vital functions. Few cases of survival exist and most survivors received post-exposure prophylaxis.¹⁴ Management in the ITU setting is appropriate.
  • Heavy sedation and analgesia.
  • Prevention and treatment of complications:
    • Cardiac arrhythmias
    • Hypotension
    • Cardiorespiratory failure
    • Fluid and electrolyte disturbance
    • Convulsions
    • Raised intracranial pressure
    • Inappropriate ADH secretion
    • Hyperpyrexia
  • Use of combinations of treatments requires further investigation. There are protocols under investigation but the small numbers of cases recruited slows up the conclusion of such trials. Antiserum, antiviral agents (including ribavirin), interferon, ketamine and other immunomodulatory therapies (rabies immunoglobulin, rabies vaccine) have failed to improve outcome.¹⁴ Steroids are contra-indicated because they increase mortality in animal studies and reduce the response to vaccination.

Prognosis

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.

Prevention^3,11,15

The cost of the full range of effective preventative measures has proved too expensive for developing nations and is expensive even for developed nations.¹³ See separate related article on rabies vaccine.

• Reduction of risk:
  • Avoid contact with potentially rabid animals.
  • Control of rabies in the animal population:
    • Vaccination of domestic dogs, cats and ferrets.¹⁶
    • Euthanasia of unvaccinated pets in contact with rabid animal (or 6 months' isolation, and vaccination 1 month prior to release).
    • The Pet Travel Scheme has replaced quarantine in the UK. This is a vaccination-based programme.
  • Vaccination and control of certain wild animals:^16,17
    • 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:³
    • Laboratory workers handling the virus.
    • Workers handling imported animals.
    • Licensed bat handlers.
    • 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 infected patients.
    • Travellers to enzoonotic areas where work involves handling animals.
    • Travellers to enzoonotic areas who may be more than 24 hours from modern medical treatment.
• Active vaccination:³
  • Human diploid cell vaccine is the vaccine of choice in the UK and USA.
  • Post-exposure vaccination has been very effective since introduction in 1980. The few failures have been ascribed to failure of wound cleaning and not giving the vaccine into the deltoid. Side-effects are usually mild and transient but applying post-exposure guidelines is important.¹⁸
  • Tissue-culture vaccines are an alternative.
  • Nervous tissue vaccines may still be used in some countries (Asia, Africa and South America). These are given as daily subcutaneous injections. They have a high incidence of side-effects and are associated with a mortality as high as 22%.
• Passive immunisation:
  • It should be used at the start of all primary post-exposure courses of rabies vaccine.
  • It should be infiltrated around the area of the wound and any remaining vaccine given into the buttocks (adults) or the thigh (children).
  • If given before the first dose of vaccine then the immune response will be impaired.

Historical perspective

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 B.C. 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 A.D. In the 16th century Spanish soldiers were described showing signs of madness after bites from vampire bats.

Document references

1. Wilde H, Khawplod P, Khamoltham T, et al; Rabies control in South and Southeast Asia. Vaccine. 2005 Mar 18;23(17-18):2284-9. [abstract]
2. Fooks AR, Brookes SM, Johnson N, et al; European bat lyssaviruses: an emerging zoonosis. Epidemiol Infect. 2003 Dec;131(3):1029-39. [abstract]
3. Immunisation against infectious disease - 'The Green Book', Dept of Health (various dates)
4. Nigg AJ, Walker PL; Overview, prevention, and treatment of rabies. Pharmacotherapy. 2009 Oct;29(10):1182-95. [abstract]
5. van der Poel WH, Lina PH, Kramps JA; Public health awareness of emerging zoonotic viruses of bats: a European perspective. Vector Borne Zoonotic Dis. 2006 Winter;6(4):315-24. [abstract]
6. Hampson K, Dushoff J, Bingham J, et al; Synchronous cycles of domestic dog rabies in sub-Saharan Africa and the impact of control efforts. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7717-22. Epub 2007 Apr 23. [abstract]
7. Song M, Tang Q, Wang DM, et al; Epidemiological investigations of human rabies in China. BMC Infect Dis. 2009 Dec 21;9:210. [abstract]
8. Recuenco S, Eidson M, Kulldorff M, et al; Spatial and temporal patterns of enzootic raccoon rabies adjusted for multiple covariates. Int J Health Geogr. 2007 Apr 11;6:14. [abstract]
9. Bronnert J, Wilde H, Tepsumethanon V, et al; Organ transplantations and rabies transmission. J Travel Med. 2007 May-Jun;14(3):177-80.
10. Srinivasan A, Burton EC, Kuehnert MJ, et al; Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med. 2005 Mar 17;352(11):1103-11. [abstract]
11. Gompf SG; Rabies, eMedicine, Oct 2008.
12. Noah DL, Drenzek CL, Smith JS, et al; Epidemiology of human rabies in the United States, 1980 to 1996. Ann Intern Med. 1998 Jun 1;128(11):922-30. [abstract]
13. Hankins DG, Rosekrans JA; Overview, prevention, and treatment of rabies. Mayo Clin Proc. 2004 May;79(5):671-6. [abstract]
14. No authors listed; Human rabies--Indiana and California, 2006. MMWR Morb Mortal Wkly Rep. 2007 Apr 20;56(15):361-5. [abstract]
15. No authors listed; Compendium of Animal Rabies Prevention and Control, 2007: National Association of State Public Health Veterinarians, Inc. (NASPHV). MMWR Recomm Rep. 2007 Apr 6;56(RR-3):1-8. [abstract]
16. Rupprecht CE, Hanlon CA, Slate D; Control and prevention of rabies in animals: paradigm shifts. Dev Biol (Basel). 2006;125:103-11. [abstract]
17. Rupprecht CE, Hanlon CA, Slate D; Oral vaccination of wildlife against rabies: opportunities and challenges in prevention and control. Dev Biol (Basel). 2004;119:173-84. [abstract]
18. Mattner F, Henke-Gendo C, Martens A, et al; Risk of rabies infection and adverse effects of postexposure prophylaxis in healthcare workers and other patient contacts exposed to a rabies virus-infected lung transplant recipient. Infect Control Hosp Epidemiol. 2007 May;28(5):513-8. Epub 2007 Mar 30. [abstract]

Acknowledgements