Info rabies

Rabies is an acute viral disease of the central nervous system (CNS) that affects all mammals and that is transmitted by infected secretions, usually saliva



Rabies is an acute viral disease of the central nervous system (CNS) that affects all mammals and that is transmitted by infected secretions, usually saliva. Most exposures to rabies are through the bite of an infected animal, but on occasion contact with a virus-containing aerosol or the ingestion or transplantation of infected tissues may initiate the disease process.


The rabies virus is a bullet-shaped, enveloped, single-stranded RNA virus that is 75 to 80 nm in diameter and belongs to the genus Lyssavirus within the rhabdovirus family. The envelope glycoproteins of rabies viruses are arranged in knoblike structures that cover the surface of the virion. Genetic and phenotypic analyses of the envelope have been used to detail the molecular epidemiology and spread of unique variants within animal species. The viral glycoproteins bind to acetylcholine receptors, contribute to the neurovirulence of rabies virus, elicit neutralizing and hemagglutination-inhibiting antibodies, and stimulate cytotoxic T cell immunity. The nucleocapsid antigen induces a complement-fixing antibody as well as T helper cell reactivity. Neutralizing antibodies to the surface glycoproteins appear to be protective and are directed at conformational epitopes of the viral envelope glycoprotein. The antibodies to rabies virus used in diagnostic immunofluorescence assays are generally directed against the nucleocapsid antigens. Isolates of rabies virus from different animal species and locales differ in their antigenic and biologic properties. These variations may account for differences in virulence between isolates. Interferon is induced by rabies virus, particularly in those tissues with high virus concentrations, and may play some role in retarding progressive infection.


Rabies is found in animals in all regions of the world except Australasia and Antarctica. Rabies exists in two epidemiologic forms: urban rabies, propagated chiefly by unimmunized domestic dogs and cats, and sylvatic rabies, propagated by skunks, foxes, raccoons, mongooses, wolves, and bats. Infection in domestic animals usually represents a “spillover” from sylvatic reservoirs of infection. Human infection occurs through contact with unimmunized domestic animals or from exposure to wild animals in locales where rabies is enzootic or epizootic. The worldwide incidence of rabies is estimated at more than 30,000 cases per year. Southeast Asia, the Philippines, Africa, the Indian subcontinent, and tropical South America are areas where the disease is especially common. In some endemic areas, 1 to 2% of autopsies yield evidence of rabies. Increased spread of terrestrial rabies (i.e., rabies in animals that walk on the ground rather than rabies in animals that fly) and increased travel to countries where urban rabies exists have made the recognition of clinical rabies and its prevention of increasing importance. While focal epidemics of terrestrial rabies have occurred in the United States and Europe, human rabies is uncommon, largely because of successful domestic-animal vaccination programs. Since 1980, 36 human cases of rabies have been diagnosed in the United States; 58% of these cases were associated with exposure to bats, while one-third were acquired through dog bites sustained outside the United States. Most persons with proven clinical rabies in this country report no history of an animal bite. More than one-third of recent cases have been diagnosed post-mortem.

In most areas of the world, the dog is the most important vector of rabies virus for humans. However, the wolf (in eastern Europe and Arctic regions), the mongoose (in South Africa and the Caribbean), the fox (in western Europe), and the vampire bat (in Latin America) may also be prominent vectors. Although rabies in wildlife is common throughout both the developed and the undeveloped world, most cases of postexposure prophylaxis are associated with domesticated animals such as dogs and cats. In the United States, local governments are charged with initiating and maintaining programs for rabies vaccination of all dogs, cats, and ferrets. Rodents and lagomorphs are rarely infected with rabies virus. Several cases of human-to-human transmission of rabies through corneal transplantation have also been documented. Bite and nonbite exposures to infected humans could theoretically transmit rabies. Because of delayed diagnosis, postexposure prophylaxis of health care workers and close contacts of cases is common.


The first event in rabies is the introduction of live virus through the epidermis or onto a mucous membrane. Initial viral replication appears to occur within striated muscle cells at the site of inoculation. The peripheral nervous system is exposed at the neuromuscular and/or neurotendinous spindles of unmyelinated sensory nerve cell endings. The virus then spreads centripetally up the nerve to the CNS, probably via peripheral nerve axoplasm, at a rate of ~3 mm/h. Viremia has been documented in experimental conditions but is thought not to play a role in naturally acquired disease. Once the virus reaches the CNS, it replicates almost exclusively within the gray matter and then passes centrifugally along autonomic nerves to other tissues¾the salivary glands, adrenal medulla, kidneys, lungs, liver, skeletal muscles, skin, and heart. Passage of the virus into the salivary glands and viral replication in mucinogenic acinar cells facilitate further transmission via infected saliva. The incubation period of rabies is exceedingly variable, ranging from 7 days to >1 year (mean, 1 to 2 months) and apparently depending on the amount of virus introduced, the amount of tissue involved, host defense mechanisms, and the actual distance that the virus has to travel from the site of inoculation to the CNS. Rates of infection and mortality are highest from bites on the face, intermediate from bites on the hands and arms, and lowest from bites on the legs. Cases of human rabies with an extended incubation period (2 to 7 years) have been reported, but they are rare. Host immune responses and viral strains also influence disease expression.

The neuropathology of rabies resembles that of other viral diseases of the CNS: hyperemia, varying degrees of chromatolysis, nuclear pyknosis, and neuronophagia of the nerve cells; infiltration by lymphocytes and plasma cells of the Virchow-Robin space; microglial infiltration; and parenchymal areas of nerve cell destruction. In experimental animal models, adenohypophyseal infection with rabies virus, with reduction in growth hormone and vasopressin release, is common. The most characteristic pathologic finding of rabies in the CNS is the formation of cytoplasmic inclusions called Negri bodies within neurons. Each eosinophilic mass measures ~10 nm and is made up of a finely fibrillar matrix and rabies virus particles. Negri bodies are distributed throughout the brain, particularly in Ammon’s horn, the cerebral cortex, the brainstem, the hypothalamus, the Purkinje cells of the cerebellum, and the dorsal spinal ganglia. Negri bodies are not demonstrated in at least 20% of cases of rabies, and their absence from brain material does not rule out the diagnosis.


The clinical manifestations of rabies can be divided into four stages: (1) a nonspecific prodrome, (2) an acute encephalitis similar to other viral encephalitides, (3) a profound dysfunction of brainstem centers that produces the classic features of rabies encephalitis, and (4) death or, in rare cases, recovery.

The prodromal period usually lasts 1 to 4 days and is marked by fever, headache, malaise, myalgias, increased fatigability, anorexia, nausea and vomiting, sore throat, and a nonproductive cough. The prodromal symptom suggestive of rabies is the complaint of paresthesia and/or fasciculations at or around the site of inoculation of virus. These sensations, which may be related to the multiplication of virus in the dorsal root ganglion of the sensory nerve supplying the area of the bite, are reported by 50 to 80% of patients.

The encephalitic phase is usually ushered in by periods of excessive motor activity, excitation, and agitation. Confusion, hallucinations, combativeness, bizarre aberrations of thought, muscle spasms, meningismus, opisthotonic posturing, seizures, and focal paralysis soon appear. Characteristically, the periods of mental aberration are interspersed with completely lucid periods, but as the disease progresses the lucid periods get shorter until the patient lapses into coma. Hyperesthesia, with excessive sensitivity to bright light, loud noise, touch, and even gentle breezes, is very common. On physical examination, the temperature may be found to be as high as 40.6°C (105°F). Abnormalities of the autonomic nervous system include dilated irregular pupils; increased lacrimation, salivation, and perspiration; and postural hypotension. Evidence of upper motor neuron paralysis, with weakness, increased deep tendon reflexes, and extensor plantar responses, is the rule. Paralysis of the vocal cords is common. Unfortunately, the presenting signs and symptoms of rabies are indistinguishable from those of other viral and neurologic diseases. Thus delays in diagnosis are frequent. The presence of hydrophobia or aerophobia (seen in about two-thirds of recent cases) increases the likelihood of antemortem diagnosis.

The manifestations of brainstem dysfunction begin shortly after the onset of the encephalitic phase. Cranial nerve involvement causes diplopia, facial palsies, optic neuritis, and the characteristic difficulty with deglutition. The combination of excessive salivation and difficulty in swallowing produces the traditional picture of “foaming at the mouth.” Hydrophobia, the painful, violent, involuntary contraction of the diaphragmatic, accessory respiratory, pharyngeal, and laryngeal muscles initiated by swallowing liquids, is seen in ~50% of cases. Involvement of the amygdaloid nucleus may result in priapism and spontaneous ejaculation. The patient lapses into coma, and involvement of the respiratory center produces an apneic death. The prominence of early brainstem dysfunction distinguishes rabies from other viral encephalitides and accounts for the rapid downhill course. The median period of survival after the onset of symptoms is 4 days, with a maximum of 20 days, unless artificial supportive measures are instituted.

If intensive respiratory support is used, a number of late complications may appear. These include inappropriate secretion of antidiuretic hormone, diabetes insipidus, cardiac arrhythmias, vascular instability, adult respiratory distress syndrome, gastrointestinal bleeding, thrombocytopenia, and paralytic ileus. Recovery is very rare and, when it occurs, gradual.

Rabies may also present as an ascending paralysis resembling the Landry/Guillain-Barre syndrome (dumb rabies, rage tranquille). Initially, this clinical pattern was reported most frequently among persons given postexposure rabies prophylaxis after being bitten by vampire bats. Paralytic rabies also occurs in Southeast Asia among persons with canine exposures.

The difficulty of diagnosing rabies associated with ascending paralysis is illustrated by cases of person-to-person transmission of the virus by tissue transplantation. Corneal transplants from donors who died of presumed Landry/Guillain-Barre syndrome produced clinical rabies in and caused the deaths of the recipients. Retrospective pathologic examinations of the brains of recipients demonstrated Negri bodies, and rabies virus was subsequently isolated from each donor’s frozen eye.


Early in the disease, hemoglobin values and routine blood chemistry results are normal; abnormalities develop as hypothalamic dysfunction, gastrointestinal bleeding, and other complications ensue. The peripheral white blood cell count is usually slightly elevated (12,000 to 17,000/uL) but may be normal or as high as 30,000/uL.

The specific diagnosis of rabies depends on (1) the isolation of virus from infected secretions [saliva or, rarely, cerebrospinal fluid (CSF)] or tissue (brain), (2) the serologic demonstration of acute infection, (3) the detection of viral antigen in infected tissue (e.g., corneal impression smears, skin biopsies, or brain), or (4) the detection of viral nucleic acid (RNA) by polymerase chain reaction (PCR). A reference laboratory evaluating antemortem samples can confirm rabies with high sensitivity and specificity. Isolation of virus from saliva, demonstration of viral nucleic acid in saliva, or detection of viral antigen in a nuchal skin biopsy specimen is most sensitive. Examination of corneal epithelium specimens appears less sensitive. In the unvaccinated person, demonstration of rabies antibodies in serum or CSF may be useful, although such antibodies may not appear until late in the course of disease. Samples of brain obtained at postmortem examination or brain biopsy should be subjected to (1) mouse inoculation studies for virus isolation, (2) fluorescent antibody (FA) staining for viral antigen, and (3) histologic and/or electron microscopic examination for Negri bodies or reverse transcription PCR for rabies virus RNA.

Postexposure rabies prophylaxis rarely elicits CSF neutralizing antibody to rabies virus. If present after prophylaxis, such antibody is usually found at a low titer (<1:64), whereas CSF titers in human rabies may vary from 1:200 to 1:160,000.


There is little to distinguish rabies from other viral encephalitides. The most helpful clue to the diagnosis is a history of a bite or other salivary exposure to a potentially infected animal. As bite exposures are infrequent among U.S. cases, a history of relatively recent travel to a rabies-endemic area should be sought. Other problems to be considered in the differential diagnosis include hysterical reactions to animal bites (pseudohydrophobia), Landry/Guillain-Barre syndrome, poliomyelitis, and allergic encephalomyelitis developing in response to rabies vaccine; this last problem is usually associated with receipt of nerve tissue-derived vaccine and usually begins 1 to 4 weeks after vaccination.


Postexposure Prophylaxis  (See Fig. 197-1) Although rabies among humans is rare in the United States, each year ~35,000 persons receive postexposure prophylaxis. The decision to initiate postexposure prophylaxis should include the following considerations: (1) whether the individual came into physical contact with saliva or another substance likely to contain rabies virus, (2) whether rabies is known or suspected in the species and area associated with the exposure (e.g., all persons within the continental United States bitten by a bat that escapes should receive postexposure prophylaxis), and (3) the circumstances surrounding the exposure (e.g., whether the bite was provoked or unprovoked). Bites associated with the feeding of an animal are considered to have been provoked.

If rabies is known or suspected to be present in the animal species involved in a human exposure, the implicated animal should be captured if possible. Any wild animal involved in a rabies exposure; any ill, unvaccinated, or stray domestic animal involved in a rabies exposure; and any animal inflicting an unprovoked bite, exhibiting abnormal behavior, or suspected of being rabid should be humanely killed. The animal’s head should be sent immediately to an appropriate laboratory for rabies FA examination. If examination of the brain by the FA technique gives negative results, it can be assumed that the saliva contains no virus, and the exposed person need not be treated. Persons exposed to wild animals that subsequently escape, that are capable of carrying rabies (bats, skunks, coyotes, foxes, raccoons, etc.), and that inhabit an area where rabies is known or suspected to be present should undergo both passive and active immunization against rabies (see below) as soon as possible after exposure.

In an area in which feline or canine rabies is not prevalent, a healthy biting dog, cat, or ferret can be confined and observed for 10 days. Persons in such an area should not begin a course of prophylaxis unless the animal develops clinical signs of rabies. If the animal becomes ill or behaves abnormally during the observation period, it should be killed for FA examination. Experimental and epidemiologic evidence suggests that animals that remain healthy for 10 days after a bite will not have transmitted rabies virus at the time of the bite. In areas of high endemicity for canine rabies, immediate examination of the animal’s brain, especially in the case of a severe bite, may be warranted. Bites of rodents, rabbits, and hares almost never require antirabies postexposure prophylaxis. Unless the exposed person can rule out a bite, scratch, or mucous membrane exposure, postexposure prophylaxis should be considered after direct contact between a human and a bat.

Postexposure prophylaxis of rabies includes rigorous cleansing and treatment of the wound and the administration of rabies vaccine together with antirabies immunoglobulin. Postexposure prophylaxis should be initiated as soon as possible after exposure. As the incubation period of rabies is quite variable, postexposure prophylaxis should be begun as long as clinical signs of rabies are not present.

1.  Wound cleansing and treatment. Thorough cleansing and treatment of the bite wound constitute an important component of rabies prevention. The wound should be scrubbed with soap and then flushed with water. Both mechanical cleansing and chemical cleansing are important. Quaternary ammonium compounds such as 1 to 4% benzalkonium chloride, 1% cetrimonium bromide, or povidone-iodine solutions should be utilized. Tetanus toxoid and antibiotic prophylaxis should be administered as needed.

2.  Passive immunization with antirabies antiserum of either equine or human origin. Postexposure antirabies vaccination should include the administration of both passive antibody and vaccine, except when the individual has previously received preexposure prophylaxis. Human rabies immune globulin (RIG) is preferred because equine antiserum may cause serum sickness. RIG is administered only once, at the beginning of the postexposure prophylaxis regimen. The recommended dose of RIG is 20 IU/kg. The dose of equine antiserum is 40 units/kg. The full dose should be thoroughly infiltrated into the area around the wound and into the wound itself. Any remaining portion of the dose is injected intramuscularly at a site distant from the vaccine.

3.  Active immunization with antirabies vaccine. Three rabies vaccines are available in the United States: (1) human diploid cell vaccine (HDCV), which can be given either intramuscularly or intradermally; (2) rabies vaccine absorbed (RVA); and (3) purified chick embryo cell vaccine. The latter two vaccines are administered intramuscularly. Each vaccine is derived from a different strain of rabies virus and prepared in a slightly different formulation. The three vaccines are considered equally efficacious and safe, and any of the three can be administered in conjunction with RIG. Five 1-mL doses of HDCV are given intramuscularly, preferably in the deltoid or anterolateral thigh area: the gluteal area should not be utilized. The five doses of HDCV should be administered within 28 days on the following schedule: days 0, 3, 7, 14, and 28. The World Health Organization also recommends 21- and 90-day injections. Severe reactions to these vaccines are uncommon. Immediate hypersensitivity responses, such as urticaria, have been reported in ~1 of every 650 recipients. Systemic reactions, such as fever, headache, and nausea, are generally mild and are reported in 1 to 4% of recipients. Local reactions, such as swelling, erythema, and induration at the injection site, occur in 15 to 20% of vaccinees. Guillain-Barre syndrome has been reported but appears to be quite rare.

In the developing world, several other effective rabies vaccines have been licensed and used extensively. They include vaccines made in chick embryonic cells, primary hamster cells, Vero cells, and duck embryonic cells. As some of these preparations are somewhat less immunogenic than the vaccines approved by the U.S. Food and Drug Administration (FDA), evaluation of serum antibodies after immunization is suggested by some authorities.

The combination of RIG and HDCV elicits high titers of neutralizing antibodies in almost all recipients. Only rarely has this regimen proved unsuccessful in preventing the development of rabies. None of the patients in whom rabies was diagnosed in the United States between 1980 and 1996 had received postexposure prophylaxis. Administration of vaccine alone appears to be associated with a higher failure rate than use of the combination, especially in severe bite exposures. Because of cost, postexposure prophylaxis consisting of intradermal injections of rabies vaccine is being used increasingly in the developing world. The combination of RIG plus 0.1-mL intradermal doses of HDCV at eight sites on day 0, four sites on day 7, and one site on days 28 and 91 produces good antibody responses and has had excellent clinical results. Alternatively, the World Health Organization has approved a regimen of two 0.1-mL doses at two intradermal sites on days 0, 3, and 7 and a 0.1-mL intradermal injection at a single site on days 21 and 90. The FDA has not approved the intradermal route for postexposure prophylaxis.

Preexposure Prophylaxis  Individuals at high risk of contact with rabies virus, including veterinarians, cave explorers, laboratory workers, and animal handlers, should receive preexposure prophylaxis with rabies vaccine. Three 1-mL intramuscular or three 0.1-mL intradermal injections of HDCV on days 0, 7, and 21 or 28 should be administered. Concomitant chloroquine administration interferes with the antibody response to rabies vaccine. Depending on the level of risk, serologic testing should be done at 6-month to 2-year intervals.

An immune complex reaction consisting of urticaria, arthralgia, arthritis, angioedema, and systemic symptoms has been reported in up to 6% of persons receiving intramuscular booster doses of HDCV. This reaction is self-limited and appears to be associated with the presence of b-propiolactone-altered human serum albumin in the vaccine and the development of IgE antibodies to this antigen.

Persons who work in high-risk areas should undergo periodic measurement of antibodies. When neutralizing titers fall below 1:5, booster doses should be given. Booster doses may be administered as a single 1-mL intramuscular or 0.1-mL intradermal injection. Postexposure prophylaxis in individuals previously given preexposure prophylaxis consists of two intramuscular doses of HDCV on days 0 and 3. RIG is not given in these situations.^


Copyright© 2001 McGraw-Hill. All rights reserved.


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