Rabies is an acute viral infection, causing progressive viral encephalomyelitis that is nearly always fatal. Transmission is usually through saliva via the bite of an infected animal, with dogs being the main transmitter of rabies to humans. Onset is generally heralded by a sense of apprehension, headache, fever, malaise and sensory changes (paresthesia) at the site of an animal bite. Excitability, aero- and/or hydrophobia, often with spasms of swallowing muscles, are frequent symptoms. Delirium with occasional convulsions follows. Such classic symptoms of furious rabies are noted in two-thirds of the cases, whereas the remaining present as paralysis of limbs and respiratory muscles with sparing of consciousness. Phobic spasms may be absent in this paralytic form. Coma and death ensue within 1–2 weeks, mainly due to cardiac failure. Diagnosis is made through specific FA staining of brain tissue or virus isolation in mouse or cell cultures. Antemortem diagnosis can be made by specific FA staining of viral antigens in frozen skin sections taken from the back of the neck at the hairline, detection of viral antibodies in serum and CSF, and specific amplification of viral nucleic acids in saliva or skin biopsies by RT-PCR. Serological diagnosis is based on neutralization tests in cell culture or in mice. Viral shedding in body secretions is intermittent and molecular studies need to be repeated if initially found negative.
Lyssaviruses, such as rabies virus, are in the family Rhabdoviridae in the genus Lyssavirus. All members of the genus are antigenically related, but use of monoclonal antibodies and nucleotide sequencing demonstrates differences according to animal species or geographical origin. Lyssaviruses in Africa (Mokola and Duvenhage) and Eurasia (European bat lyssaviruses) have been associated with fatal encephalitis. A lyssavirus, first identified in 1996 in several species of flying foxes and bats in Australia, has been associated with 2 human deaths from rabies. These viruses, named Australian bat lyssaviruses, are closely related, but not identical, to classical rabies virus. Illnesses suspected due to rabies by other lyssaviruses may be diagnosed by the standard FA test on brain tissue or by suggested antemortem tests. Several other lyssaviruses (e.g. Aravan virus, Irkut virus, Khujand virus, Lagos bat virus, West Caucasian bat virus) have been characterized as etiological agents of rabies in mammals, but have not so far been identified in human infections.
Worldwide, more than 10 million human exposures are estimated, and an estimated 55 000 rabies deaths occur each year, almost all in developing countries, particularly in Asia (31 000 deaths) and Africa (24 000 deaths). Most human deaths follow dog bites for which adequate post-exposure prophylaxis was not or could not be provided. In Latin America, a regional dog rabies control program coordinated by PAHO since 1983 has led to a reduction of almost 95% in the number of human deaths, with only 26 cases reported in 2007, 46% of which followed contacts with hematophagous bats. During the past 12 years, although reduction of the numbers of human cases have been reported in several Asian countries (particularly Thailand), drastic increases have occurred in China—where since 1996 the number of notified human rabies deaths has continuously increased, reaching 3 300 in 2006—and Viet Nam. Western, central and eastern Europe, including Russia, report less than 50 human rabies deaths annually. In the USA between 2000 and 2007, 20 of 25 human deaths from rabies were acquired domestically. Of those infected within the USA, almost all were bat-associated rabies (as identified by viral variant analysis). Rabies can present in atypical forms, and medical personnel unfamiliar with the disease may misdiagnose it. This is one factor in underreporting of this disease worldwide.
Rabies is a zoonotic disease, primarily associated with the bite of infected mammals. Given the global distribution of bat rabies, few areas are truly free of autochthonous rabies in the animal population. Some sites include insular locations in the western Pacific and parts of the Caribbean. Dogs transmit rabies in most developing countries, whereas in many developed countries, rabies is a disease of wild carnivores, with sporadic spillover infection to domestic animals. In Canada, and the USA, oral immunization of free-ranging wild carnivores has controlled rabies over large areas, via the distribution of vaccine-laden baits. By 2000, many western European countries had likewise successfully eliminated fox rabies by oral immunization.
All mammals are susceptible. Reservoirs and important vectors include wild and domestic Canidae, such as dogs, foxes, coyotes, wolves and jackals; also, skunks, raccoons, raccoon dogs, mongooses and other common carnivores, such as cats in North America. In developing countries, dogs remain the principal reservoir. Infected populations of vampire, frugivorous and insectivorous bats occur in Mexico and Central and South America, and infected insectivorous bats are present throughout Canada, the USA and Eurasia. In Africa and Australia, infected frugivorous and insectivorous bat species are involved in transmission. Many other mammals, such as rabbits, squirrels, chipmunks, rats, mice and opossums are very rarely infected.
Modes of transmission
The most common form of exposure is virus-laden saliva from a rabid animal introduced though a bite or scratch (and very rarely into a fresh break in the skin or through intact mucous membranes). Person-to-person transmission is theoretically possible, but is rare and not well documented. Several cases of rabies transmission by transplant of cornea, solid organs and blood vessels from persons dying of undiagnosed CNS disease have been reported from Asia, Europe and North America. Airborne spread has been suggested in a cave where heavy infestations of bats were roosting, and demonstrated in laboratory settings, but this occurs very rarely. Transmission from infected vampire bats feeding on domestic animals is common in Latin America. Rabid insectivorous or frugivorous bats can transmit rabies to terrestrial animals, wild or domestic.
The period is highly variable, but usually 3–8 weeks, and very rarely as short as a few days, or as long as several years. The length of the incubation period depends in part on wound severity, wound location in relation to nerve supply, and relative distance from the brain; the amount and variant of virus; the degree of protection provided by clothing; and other factors.
Period of communicability
Defined periods of communicability of animal hosts are only known with reliability in domestic dogs, cats, and ferrets, and are usually for 3–7 days before onset of clinical signs (rarely over 4 days) and throughout the course of the disease. Longer periods of excretion before onset of clinical signs (14 days) have been observed with certain canine rabies virus variants in experimental infections, but these are the exception. Excretion in other animals is highly variable: for example, in one study bats shed virus for 12 days before evidence of illness, while in another, skunks shed virus for at least 8 days before onset of clinical signs.
All mammals are susceptible to varying degrees; the degree of susceptibility may be influenced by the virus variant as well as by certain host parameters (age, health, nutrition, etc.). Humans may be more resistant to infection than several other animal species; for example, a study in the Islamic Republic of Iran showed that, of those bitten by proven rabid animals and not treated, about 40% developed the disease.
Methods of control
- Preventive measures: Many preventive measures are possible at the level of the primary animal host(s) and transmitter(s) of rabies to humans. Such measures are part of a comprehensive rabies control program.
- Register, license and vaccinate all owned dogs, and other pets when feasible, in enzootic countries; control ownerless animals and strays. Educate pet owners and the public on the importance of local community responsibilities (e.g. pets should be leashed in congested areas when not confined on the owner's premises; strange-acting or sick animals of any species—domestic or wild—should be avoided and not handled; animals that have bitten a person or another animal should be reported to relevant authorities, such as the police/local health departments; if possible, such animals should be confined and observed as a preventive measure; and wildlife should be appreciated in nature and not be kept as pets). Where animal population reduction is impractical, animal contraception and repetitive vaccination campaigns may prove effective.
- Maintain active surveillance for animal rabies. Laboratory capacity should be developed to perform FA diagnosis on all wild mammals involved in human or domestic animal exposures, and all domestic animals clinically suspected of having rabies.
- Detain and observe for 10 days any healthy-appearing dog or cat known to have bitten a person (stray or ownerless dogs and cats may be euthanized and examined for rabies by fluorescent microscopy); dogs and cats showing suspicious clinical signs of rabies should be euthanized and tested for rabies. If the biting animal was infective at the time of the bite, it usually develops signs of rabies within 4–7 days, such as change in behavior, excitability or paralysis, followed by acute death. All wild mammals that have bitten a person should be euthanized and the brain examined for evidence of rabies.
- In a timely manner, submit to a qualified laboratory the intact head of suspect animals, packed in ice (not frozen), for viral diagnosis.
- Euthanize unvaccinated domestic animals bitten by known rabid animals; if detention is elected, hold the animal in a secure facility for at least 6 months under veterinary supervision, and vaccinate against rabies 30 days before release. If previously vaccinated, booster immediately with rabies vaccine, and detain for at least 45 days.
- Immunize wild carnivore reservoirs and free-ranging domestic dogs, using vaccine-laden baits containing attenuated or recombinant rabies viral vectors, as utilized in Europe and North America.
- Cooperate with wildlife conservation authorities in programs to reduce the carrying capacity of wildlife hosts of sylvatic rabies, and to reduce exposures to domestic animals and human populations—such as in circumscribed enzootic areas near campsites, and in areas of dense human habitation.
- Vaccinate individuals at high risk of exposure (e.g. veterinarians and veterinary technicians, animal control staff, wildlife researchers, cavers, staff of quarantine kennels, laboratory and field personnel working with rabies virus, and long-term travelers to rabies-endemic areas). Such persons should receive pre-exposure immunization, using potent and safe cell-culture vaccines (CCVs). Vaccine can be administered in doses of 1.0 ml or 0.5 ml intramuscularly (IM) on days 0, 7 and 21 or 28. Post-immunization serological testing is advisable every 6 months to 2 years, depending upon the defined level of exposure, as long as the risk remains. Results with intradermal (ID) immunization (using WHO recommended schedules) for Human Diploid Cell rabies Vaccine (HDCV), Purified Chick Embryo (PCECV) and Purified Vero Cell Vaccines (PVRVP) have been equivalent to what is expected from the intramuscular schedule. Antibody response to ID immunization has been less than ideal in some groups receiving chloroquine for antimalarial chemoprophylaxis. Although the comparative immune response has not been evaluated for antimalarials structurally related to chloroquine (e.g. mefloquine, hydroxychloroquine), similar precautions for individuals receiving these drugs should be followed. The human diploid cell vaccine (HDCV) was the original gold standard for modern human rabies prophylaxis, but is too expensive for developing countries. Other cell-culture vaccines fulfilling basic WHO requirements for the ID route, such as purified vero cell and chick embryo cell vaccines, are widely and successfully used in canine rabies-endemic countries.
If a risk of exposure continues, single booster doses are given, or—preferably—serum is tested at regular intervals for neutralizing antibody detection, dependent upon relative risk of exposure, and booster doses are given only when indicated.
- Prevention of rabies after animal bites (“post-exposure prophylaxis” or PEP) consists of the following:
- First aid: Clean and flush the wound immediately with soap or detergent and water (or water alone), then apply either 70% ethanol, tincture of aqueous solution of iodine or povidone iodine, or Dakins solution (household bleach: 3 tablespoons of bleach plus ½ teaspoon baking soda in 1 liter of boiled water). The wound should not be sutured unless unavoidable. Sutures, if required, should be placed after local infiltration of antiserum (see 9b); they should be loose, and should not interfere with free bleeding and drainage.
- Specific treatment (serum and vaccine): Specific passive prophylaxis in humans is provided by administration of human (HRIG) or equine (ERIG) rabies immune globulin at the site of the bite as soon as possible after exposure, to neutralize the virus; and is followed by vaccine at a different site to elicit active immunity. Animal studies suggest that human disease caused by the Australian bat lyssavirus may be prevented by rabies vaccine and RIG, and such PEP is recommended for persons bitten or scratched by any bat in Australia. Although PEP may not always be effective for the prevention of bat lyssaviruses throughout the world, it should always be performed.
Passive immunization: HRIG should be used in a single dose of 20 IU/kg, and ERIG in a single dose of 40 IU/kg. All or as much as possible of this should be infiltrated into and around the bite wound; the remainder, if any, should be given IM. Where serum of animal origin (ERIG) is used, an intradermal or subcutaneous test dose has been used preceding administration to detect potential allergic sensitivity, but the utility of this testing for predictive risk has been questionable.
WHO-approved cell-culture vaccines should be applied according to the WHO and USA-CDC approved “Essen Regimen,” in 5 IM doses of 0.5 or 1.0 ml on days 0, 3, 7, 14 and 28 (see manufacturer's instructions), in the deltoid region or lateral thigh muscles. This is to start as soon as possible after exposure. In Europe, Asia, Africa, South and Central America, a second WHO-approved regimen is widely used and found to be safe and effective; this is referred to as the “2-1-1” or “Zagreb” Regimen, and consists of two full intramuscular doses at two sites on day 0, and one injection each on days 7 and 21. It saves one vaccine dose and one clinic visit.
Reduced-dose, WHO-approved, multi-site intradermal post-exposure schedules have been approved by local authorities in several rabies-endemic countries of Asia and Africa where the cost of vaccine is a significant deterrent to proper post-exposure prophylaxis. WHO recommends 2 ID multi-site regimens with cell-culture vaccines known to be safe and immunogenic: i) the 2-site Thai Red Cross regimen (2-2-2-2); and ii) the 8-site Oxford regimen (8-0-4-0-1-1). If properly applied using potent modern vaccines, these schedules result in an antibody response equivalent to that seen with the two WHO-approved intramuscular regimens.
It has been well documented that subjects with severe immunodeficiency (very low CD4 counts) will not respond well to rabies vaccination. Some may not develop neutralizing antibody at all. Careful wound cleansing and the use of immunoglobulin is thus of great importance in such patients. Vaccination must be administered in the usual dose. A serum specimen should be collected at the time when the last dose of vaccine is administered and tested for rabies antibodies. If sensitization reactions appear in the course of immunization, consult the health department or infectious disease consultants for guidance. If the person has had a previous full course of pre- or post-exposure rabies immunization with an approved vaccine (see 9A8), only 2 doses of vaccine need to be given—one immediately, and one 3 days later. In the previously vaccinated person, RIG and ERIG are not used.
- The combination of local wound treatment, passive immunization with RIG and active vaccination is recommended for all severe exposures (category III, see end of this item), virtually guaranteeing complete protection. Pregnancy and infancy are never contraindications to post-exposure prophylaxis (PEP). Persons presenting even months after the bite must be dealt with in the same way as recent exposures. Factors to be considered in the initiation of PEP are nature of the contact; rabies endemicity at site of encounter or origin of animal; animal species involved; vaccination/clinical status; availability of animal for observation; type of vaccine used; and laboratory results of animal for rabies, if available.
- Modern cell-culture vaccines (CCVs) are considered to be safe and well tolerated, although reported reaction rates to primary immunization have varied with the monitoring system. Following IM immunization with the human diploid cell vaccine, mild and self-limited local reactions, such as pain at the site of injection, redness, and swelling, occur in 21%–74% of cases. Mild systemic reactions, such as fever, headache, dizziness, and gastrointestinal symptoms, occur in 5%–40% of cases, and systemic hypersensitivity following booster injections occurs in 6% of vaccines, but is less common following primary immunization. When further purification steps are added, systemic hypersensitivity reactions become very rare. With chick embryo and Vero cell-based vaccines, the rates of local and mild systemic reactions are similar to those of the human diploid cell vaccine, but no systemic hypersensitivity reactions have been reported. Compared with IM vaccination, the ID application is at least as safe and well tolerated, although local irritation may be more frequent. No significant adverse reactions have been attributed to HRIG; however, antiserum from a nonhuman source produces serum sickness in 5%–40% of recipients. Newer, commercially produced purified animal globulins, in particular purified equine globulin, have only a 1–6% risk of serum sickness reactions. The commonly used skin test for ERIG will not predict serum sickness. Serious anaphylaxis is extremely rare with purified ERIG products (2 in over 150 000 cases in one series). The risk of contracting fatal rabies outweighs the risks for allergic reactions.
- Control of patient, contacts and the immediate environment:
- Report to local health authority: Obligatory case report required in most countries, Class 2 (see Reporting).
- Isolation: Contact with salivary secretions of a rabid patient should be avoided during the illness.
- Concurrent disinfection: Of saliva and articles soiled therewith. Although transmission from a patient to attending personnel has not been documented, immediate attendants should be warned of the potential hazard of infection from saliva, and should wear gloves, protective gowns, and other appropriate personal protection equipment to avoid exposure from a coughing patient.
- Quarantine: Not applicable.
- Immunization of contacts: Contacts who receive a bite or have an open wound or mucous membrane exposure to the patient's saliva should receive specific PEP (see 9A9b).
- Investigation of contacts and source of infection: Search for rabid animals and for people and other animals bitten.
- Specific treatment: For clinical rabies, intensive supportive medical care.
- Epidemic (epizootic) measures: Applicable only to animals; a sporadic disease in humans.
- Establish control area under authority of laws, regulations and ordinances, in cooperation with appropriate human, agricultural and wildlife conservation authorities.
- Immunize dogs and cats through officially sponsored, intensified mass programs that provide immunizations at temporary and emergency stations. For protection of other domestic animals, use approved vaccines appropriate for each animal species.
- In urban areas of industrialized countries, strict enforcement of regulations requiring collection, detention and euthanasia of ownerless and stray dogs, and of non-immunized dogs found off owners' premises; control of the dog population by castration, spaying or drugs have been effective in breaking transmission cycles.
- Immunization of wildlife through baits containing vaccine has contained red fox rabies in western Europe and southern Canada, and coyote, gray fox, and raccoon rabies in the USA.
- Disaster implications: A potential problem exists if the disease is freshly introduced or enzootic in an area where there are many stray dogs or wild reservoir animals. Similarly, in disaster areas—for example after hurricanes or tsunamis—many stray animals may occur after human evacuations, with subsequent bites to animal control or humane society personnel taking part in future rescue attempts.
- International measures: For more information, see: Post-Exposure Prophylaxis Guide.
- Strict compliance by common carriers and travelers with national laws and regulations (see International travel and Health, WHO 2007, chapter 5, p 73). Immunization of animals, certificates of health and origin, and microchip identification of animals may be required.
- WHO Collaborating Centres and other international organizations and institutions prepared to collaborate with national services on request. See WHO Expert Consultation on Rabies, first report, TRS 931, WHO, Geneva, 2005, annex 3, pp 76–80. More information on Collaborating Centres can be found at http://www.who.int/collaboratingcentres/database/en/.
[CCDM19: T. Hemachuda, F. Meslin, C. Rupprecht, H. Wilde]
[CCDM18: F. Meslin]
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