Introduction and Definitions
Rabies is a viral infection which is transmitted in the saliva of infected mammals; it causes an acute encepha-lomyelitis that is almost always fatal. Human pathogens of medical importance are members of the genus Lys-savirus and Vesiculovirus. Almost all cases of human rabies, a lyssavirus infection, are caused by a bite of a rabid animal. Although the risk of rabies is highest in countries of most of Asia, Africa and South America and it is rare as a human infection in Western Europe and North America, every year, for example, up to 40 000 people receive postexposure prophylaxis in the USA.
Rabies virus is a member of the family Rhabdoviridae, with a characteristic bullet shape. There are some 80 other bullet-shaped viruses which infect animals (including fish), plants, invertebrates and insects. For practical purposes, only Rabies virus is considered below, but other members of the Lyssavirus group which include the serologically related Lagos bat virus, Mokola virus and Duvenhage virus in Africa, and Duvenhage virus in Europe (European bat virus) should be noted.
Rabies virus is a negative-sense, non-segmented, single-stranded RNA virus measuring about 75 x 180 nm. The helical nucleocapsid of 30-35 coils is surrounded by an outer lipid bilayer membrane with surface projections about 8 nm in length. The viral genome encodes five proteins, three of which are associated with the ribonuc-leoprotein complex, which, together with the viral RNA, aggregate in the cytoplasm of infected neurons to form the characteristic Negri bodies. The matrix protein (M) and the glycoprotein (G) are associated with the viral envelope. The glycoprotein is required for virus infectivity and recognises specific cell receptors. It is also the only rabies virus protein known to induce neutralising antibody.
The effect of chemical agents on rabies virus is underlined by the importance of thorough cleansing of the wound with soap or detergent. The virus is destroyed by quaternary ammonium disinfectants, 1% soap solutions, ionic and nonionic detergents, 5% iodine, common organic solvents such as 45% alcohol, ether and chloroform, formalin and ^-propriolactone.
Isolates of rabies virus from naturally infected animals, i.e. wild-type virus, are referred to as 'street' virus, and viruses adapted by laboratory passage in animals or cell culture are referred to as 'fixed' virus.
Epidemiology, Geographical Distribution and Reservoir of Infection
Human rabies is almost always caused by a bite or contamination of surface wounds by virus in saliva, but infection through intact mucosa, for example of the mouth or the conjunctiva, can occur. Aerosol transmission has been implicated in human infection in bat-infested caves and in laboratory accidents. Human-to-human transmission has been reported rarely, for example, by transplantation of infected corneas, and in the older literature. Rabies has not been reported in nursing and medical staff, but nevertheless there is a risk of exposure by bite or by contaminated saliva during airway care, and appropriate precautions should be exercised. It should also be noted that definitive animal exposure or incident cannot be identified in a significant number of human cases.
Rabies is primarily a disease of animals and most human cases occur in the developing world. The only areas free of animal rabies include Australia and New Zealand and islands such as the UK and Ireland, and the Pacific Islands. Rabies is most prevalent among wild foxes, wolves and jackals, followed by domestic dogs, skunks, cats, farm animals, bats and others. The principal reservoir in Africa, Central America (including Mexico), South America and Asia is the unvaccinated domestic dog. There is little information about rabies in wildlife in tropical areas. The major reservoir of infection in Europe is the red fox, and rabies has been identified in Central European deer. The major sources in the USA include skunks, bats and racoons.
Although rabies virus receptors appear to coincide with the distribution of acetylcholine receptors, the virus can enter the cell independently of these receptors. The virus may access the peripheral nerves directly or it may replicate in the muscle tissue, remaining at or near the site of introduction into the host for most of the incubation period, essentially at motor endplates, replicating in monocytes and later involving the peripheral nerves via the neuromuscular junctions. The virus then moves cen-tripetally to the central nervous system for replication. Subsequently it moves centrifugally to many tissues, including the salivary glands. Pathological changes in the brain are not profound, apart from the pathognomonic Negri bodies. Few neurons are involved, there is limited tissue necrosis and some perivascular cuffing.
The incubation period is variable, ranging from a few days to several years, but in most cases the range is 30-90 days. The development of the infection depends on the severity of the exposure, the site of the bite and whether the wounds were inflicted through bare skin, and other factors.
Prodromal symptoms are nonspecific, although behaviour disturbances are often present, including anxiety, depression, hyperactivity, aggression, intolerance to tactile, auditory and visual stimuli, or delirium. Later symptoms of acute encephalitis appear, and clinical features may be confused with tetanus or cerebral malaria, poliomyelitis, botulism, or others. Clinical neurological findings have been classified as either 'furious' or 'paralytic'. Furious rabies is the most common form; it is characterised by spasms in response to external stimuli, which may be tactile, visual, auditory or olfactory and include hydrophobia and aerophobia. Spasms alternate with periods of calm and lucidity, agitation and confusion and dysfunction of the autonomic nervous system. Paralytic rabies involves clinical features ranging from paralysis of one limb to quadriplegia. The disease progresses to severe neurological complications, coma and death. Clinical differential diagnosis of rabies should be considered in every patient with unexplained encephalitits or with neurological signs, particularly where there is a history of animal bite or possible exposure in a country where rabies is endemic.
Diagnosis in the laboratory is established by the detection of rabies antigen, antibody, rabies viral RNA or the isolation of the virus. Rapid diagnosis antemortem is by detection of rabies antigen by direct immunofluorescence in a skin biopsy from the nape of the neck. Other freshly obtained tissues may be used. The virus can be isolated in tissue culture by inoculation of a murine neuroblastoma cell line (NAC 1300) or by inoculation of laboratory rodents. PCR and other molecular tests can be employed. Detection of rabies virus neutralising antibody by a rapid fluorescence focus inhibition test in the serum of unvac-cinated persons is also diagnostic, and the presence of antibody in the cerebrospinal fluid confirms the diagnosis. In vaccinated individuals differentiation between antibody due to vaccination or disease is not possible, but vaccination does not produce typically CSF antibody.
Management, Treatment and Prevention
The basic approach to the control of rabies is control of infection of animals where possible, prevention of exposure and immunisation. Treatment of human rabies is based on postexposure management of the wound and prophylaxis.
Methods for the control of rabies in animals are described in a compedium prepared by the National Associ ation of State Public Health Veterinarians of the USA (Compendium of Animal Rabies Control, 1999).
Note that an unprovoked attack by an animal is more likely than a provoked attack to indicate that an animal is rabid and great care must be exercised to avoid contact with stray or unvaccinated dogs, cats and ferrets, particularly in countries where rabies is endemic and vaccination of domestic animals is unlikely.
Attack by a rabid animal constitutes a medical emergency. Immediate and thorough washing of all bite wounds and scratches with soap and water and, if available, a virucidal solution as described above, such as quaternary ammonium disinfectants, ionic and nonionic detergents or 5% iodine, are most important. Avoid closure of the wound surgically unless suture of a large wound is essential because of the size of the wound, the potential for bacterial infection and cosmetic reasons.
Postexposure antirabies immunisation should include the administration of both passive antibody in the form of specific antirabies immunoglobulin and active vaccination with a cell culture vaccine. A desirable postexposure prophylaxis regimen is described in the recommendations of the US Advisory Committee on Immunization Practices (1999b). Briefly, in those not previously vaccinated against rabies, immediate wound cleansing must be followed by:
• Administration of 20IUkg_1 body weight of anti-rabies immunoglobulin. If feasible anatomically, the full dose should be infiltrated around the wound(s), and any remaining amount should be given intramuscularly but at a distant site from the site of vaccine administration.
• Human diploid cell vaccine, rabies vaccine adsorbed or purified chick embryo cell vaccine should be given intramuscularly into the deltoid muscle—1.0 ml immediately and on days 3, 7, 14 and 28.
In the case of a patient who has been vaccinated previously with any of the above vaccines or with any other type of rabies vaccine, and a documented history of antibody response to the prior vaccination, the following regimen applies after immediate wound cleansing:
• Antirabies immunoglobulin should not be given.
• Human diploid cell vaccine, rabies vaccine adsorbed or purified chick embryo cell vaccine should be given intramuscularly into the deltoid muscle immediately (day 0) and on day 3 in a dose of 1.0 ml. The gluteal muscles should never be used because the resulting antibody titres are lower than those achieved by administration into the deltoid muscle.
Pre-exposure immunisation should be offered to high-risk groups, which include veterinary surgeons and veterinary nurses and assistants, animal handlers, wildlife keepers and handlers, and certain laboratory workers. Pre-exposure immunisation should be considered for other persons who may come into frequent contact with animals potentially infected with rabies or who travel to or reside in areas where animal rabies, particularly dog rabies, is enzootic and immediate access to appropriate medical care is or may be limited.
Primary intramuscular vaccination involves three 1.0 ml injections of one of the vaccines listed above given intramuscularly into the deltoid muscle on days 0, 7, and 21 or 28. Intradermal primary vaccination of three 0.1 ml doses of human diploid cell vaccine, one each on days 0,7, and 21 or 28 is an alternative schedule.
Note that malaria prophylaxis with chloroquine phosphate (and possibly structurally related compounds, which have not yet been investigated for this effect) decreases the antibody response to antirabies human di-ploid cell vaccine given concomitantly.
Pre-exposure booster doses of vaccine must be given to laboratory research workers working with rabies virus or those in vaccine production units. Rabies antibody should be measured every 6 months and a booster dose given according to the neutralisation antibody titre.
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