Chapter 17: Rabies

Rabies is an acute fatal viral illness of the central nervous system (CNS). The word rabies is derived from the Latin verb “to rage,” which suggests the appearance of the rabid patient. It can affect all mammals and is transmitted between them by infected secretions, most often by bite. It was first recognized more than 3000 years ago and has been the most feared of infectious diseases. It is said that Aristotle recognized that rabies could be spread by a rabid dog.

VIROLOGY

The rabies virus is a rhabdovirus, which is a bullet-shaped, enveloped, RNA virus, 70 nm in diameter × 180 nm in length, of the Lyssavirus genus and Rhabdoviridae family (Figure 17–1). The helical nucleocapsid (N) is composed of a single-stranded, negative-sense RNA genome and an RNA-dependent RNA polymerase enclosed in a matrix (M) protein covered by a lipid bilayer envelope containing knob-like glycoprotein (G). The knob-like glycoprotein excrescences, which elicit neutralizing and hemagglutination-inhibiting antibodies, cover the surface of the virion. In the past, a single antigenically homogeneous virus was believed to be responsible for all rabies; however, differences in cell culture growth characteristics of isolates from different animal sources (bats, cats, dogs, foxes, skunks), some differences in virulence for experimental animals, and antigenic differences in surface glycoproteins have indicated strain heterogeneity among rabies virus isolates. These studies may help to explain some of the biologic differences as well as the occasional case of “vaccine failure.” Other pathogens in the rhabdovirus group include vesicular stomatitis virus, which is an animal virus but may also occasionally infect humans (see Chapter 16).

Rabies virus is transmitted from the bite of an animal (usually a rabid dog or wild animal) and multiplies initially at the site of entry in muscle cells, and then the virus travels to the CNS to replicate in the brain cells. Rabies virus G protein binds to the acetylcholine or neural cell adhesion molecule (NCAM) receptor present on the cell surface. The virus is internalized followed by fusion of the viral envelope with the endosomal membrane and uncoating and release of the nucleocapsid in the cytoplasm. Because rabies virus is a negative-sense RNA virus, virion-associated RNA-dependent RNA polymerase transcribes the genome to make several mRNAs in the cytoplasm. These mRNAs are translated into various proteins, including nucleocapsid, matrix, RNA polymerase, and G glycoproteins. The G glycoproteins are expressed on the infected cell surface membranes. After replication of viral RNA genomes directed by the viral RNA-dependent RNA polymerase, the progeny virions are assembled in the cytoplasm. The nucleocapsid protein binds the RNA genome and packages the viral RNA-dependent RNA polymerase. This nucleocapsid complex associates with the matrix protein, and the lipid bilayer envelope containing G protein is acquired as the progeny virions bud through the plasma membrane.

RABIES

Rabies exists in two epizootic forms, urban and sylvatic. The urban form is associated with unimmunized dogs or cats, and the sylvatic form occurs in wild skunks, foxes, wolves, raccoons, and bats, but not rodents or rabbits. Introduction of an infected animal into a different geographic area can lead to infection of many new members of that species (Figure 17–2). For example, raccoon hunters apparently are to blame for the sudden appearance of raccoon rabies in West Virginia and Virginia in 1977. Before that time, the nearest cases of raccoon rabies were found several hundred miles away in South Carolina. The hunters are believed to have imported infected raccoons from another state. Since 1977, raccoon rabies has spread from West Virginia and Virginia to 12 northeastern states.

Two epizootic forms of rabies: urban (unimmunized dogs and cats) and sylvatic (wild bats, foxes, raccoons, skunks, wolves)

Human infection, or the much more common infection of cattle, is incidental, is blind ended, and does not contribute to maintenance or transmission of the disease. In the United States, more than 75% of reported cases of rabies in animals occur among wildlife. Human exposures may be from wild animals or from unimmunized dogs or cats. In recent years, there has been a decrease in US cases to less than two per year, and bat exposure has been the source in almost all cases despite a resurgence of rabies in skunks and raccoons. An occasional case has resulted from aerosol exposure (eg, bat caves and no bite). Domestic animal bites are very important sources of rabies in developing countries because of lack of enforcement of animal immunization. Infection in domestic animals usually represents a spillover from infection in wildlife reservoirs. Human infection tends to occur where animal rabies is common and where there is a large population of unimmunized domestic animals. Worldwide, the occurrence of human rabies is estimated to be more than 55 000 fatal cases per year mostly in Asia and Africa, with the highest attack rates in Southeast Asia, the Philippines, and the Indian subcontinent. Almost all of these cases result from dog bites. Human-to-human transmission of rabies has been documented via transplanted corneas and solid-organ transplantation. In theory, infected humans could potentially transmit rabies to uninfected humans via bite or nonbite, but such cases have not been reported.

The sequence of events of the pathogenesis of rabies virus infection is depicted in Figure 17–3. The essential first event in human or animal rabies infection is the inoculation of virus through the epidermis, usually as a result of an animal bite. Inhalation of heavily contaminated material, such as bat droppings, can also cause infection. The incubation period is between 10 days and 1 year (average 20-90 days). Rabies virus first replicates in striated muscle tissue at the site of inoculation. Immunization at this time is presumed to prevent migration of the virus into neural tissues. In the absence of immunity, the virus then enters the peripheral nervous system at the neuromuscular junctions and spreads to the CNS, where it replicates exclusively within the gray matter. It then passes centrifugally along autonomic nerves to reach other tissues, including the salivary glands, adrenal medulla, kidneys, and lungs. Passage into the salivary glands in animals facilitates further transmission of the disease by infected saliva. The neuropathology of rabies resembles that of other viral diseases of the CNS, with infiltration of lymphocytes and plasma cells into CNS tissue and nerve cell destruction. The pathognomonic lesion is the Negri body (Figure 17–4), an eosinophilic cytoplasmic inclusion distributed throughout the brain, particularly in the hippocampus, cerebral cortex, cerebellum, and dorsal spinal ganglia.

The incubation period for rabies ranges from 10 days to 1 year, depending on the amount of virus introduced, the amount of tissue involved, the host immune mechanisms, the innervation of the site, and the distance that the virus must travel from the site of inoculation to the CNS. Thus, the incubation period is generally shorter with face wounds than with leg wounds. Immunization early in the incubation period frequently aborts the infection.

CLINICAL ASPECTS

Rabies in humans usually results from a bite by a rabid animal or contamination of a wound by its saliva. It presents as an acute, fulminant, fatal encephalitis; human survivors have been reported only occasionally. The clinical stages of rabies infection are summarized in Table 17–1. After an average incubation period of 20 to 90 days (range 10 days to 1 year), the disease begins as a nonspecific illness marked by fever, headache, malaise, nausea, and vomiting known as prodrome stage. Abnormal sensations at or around the site of viral inoculation occur frequently and probably reflect local nerve involvement. In the acute neurologic stage, the onset of encephalitis is marked by periods of excess motor activity and agitation. Hallucinations, combativeness, muscle spasms, signs of meningeal irritation, seizures, and focal paralysis occur. Periods of mental dysfunction are interspersed with completely lucid periods; however, as the disease progresses, the patient lapses into coma. Autonomic nervous system involvement often results in increased salivation. Brainstem and cranial nerve dysfunction is characteristic, with double vision, facial palsies, and difficulty in swallowing. The combination of excess salivation and difficulty in swallowing produces the fearful picture of “foaming at the mouth.” Hydrophobia, the painful, violent involuntary contractions of the diaphragm and accessory respiratory, pharyngeal, and laryngeal muscles, initiated by swallowing liquids including water, is seen in about 50% of the cases. Involvement of the respiratory center produces respiratory paralysis, the major cause of death. Occasionally, rabies may appear as an ascending paralysis resembling Guillain-Barré syndrome. Once symptoms have developed, no drug or vaccine administration can improve survival. The median survival after onset of symptoms is 4 days, with a maximum of 20 days unless artificial supportive measures are instituted. Recovery is exceedingly rare.

The CSF of a rabies patient shows minimal to no abnormalities with some patients exhibiting a lymphocytic pleocytosis (5-30 cells/mm³). The test of choice in a live patient is detection of rabies antigen by immunofluorescent stain of a biopsy from the nape of the neck. PCR of CSF or saliva may supplant the neck biopsy. Laboratory diagnosis of rabies in animals or deceased patients is accomplished by demonstration of virus in brain tissue. Viral antigen can be demonstrated rapidly by immunofluorescence procedures. Intracerebral inoculation of infected brain tissue or secretions into suckling mice results in death in 3 to 10 days. Histologic examination of their brain tissue shows the Negri bodies in 80% of the cases; electron microscopy may demonstrate both the Negri bodies and rhabdovirus particles. Specific antibodies to rabies virus can be detected in serum, but generally only late in the disease.

Prevention is the mainstay of controlling rabies in humans by immediately starting the rabies vaccination process. With symptomatic rabies, intensive supportive care has resulted in four or five long-term survivals; despite the best modern medical care, however, the mortality rate still exceeds 90%. In addition, because of the infrequency of the disease, many patients die without definitive diagnosis. Human hyperimmune antirabies globulin, interferon, and vaccine do not alter the disease once the symptoms have developed. Postexposure prophylaxis is considered as a treatment for rabies exposure to humans after bites from rabid or wild animals.

In a controversial experimental treatment strategy in 2004, known as the Wisconsin or Milwaukee protocol, a 15-year old patient with rabies symptoms was placed in a chemically induced coma and treated with antivirals (ribavirin and amantadine). The coma was reversed in the patient after her immune system started making rabies antibodies. The patient became free of rabies virus and survived.

In the late 1800s, Pasteur, noting the long incubation period of rabies, suggested that a vaccine to induce an immune response before the development of disease might be useful in prevention. He apparently successfully vaccinated Joseph Meister, a boy severely bitten and exposed to rabies, with multiple injections of a crude vaccine made from dried spinal cord of rabies-infected rabbits. This treatment emerged as one of the best-known and most noteworthy accomplishments in the annals of medicine. It is now believed that vaccination induces antibody that is either neutralizing or inhibits cell-to-cell spread of virus. Natural infection does not lead to an early immune response and limitation of viral migration, because the virus is replicating in muscle or neural tissue and lymphocytes do not access these sites. Cytotoxic T lymphocytes are also induced by vaccine and appear to be directed against an antigen of the virus.

Currently, the prevention of rabies is divided into preexposure and postexposure prophylaxis. There are currently two inactivated (killed) vaccines licensed in the United States: human diploid cell vaccine (an attenuated strain of rabies virus grown in human diploid cell culture and inactivated by β-propiolactone) and purified chick embryo cell vaccine (fixed rabies virus strain grown in primary cultures of chicken fibroblasts and inactivated by β-propiolactone). Preexposure prophylaxis is recommended for individuals with high risk of contact with rabies virus, such as veterinarians, spelunkers, laboratory workers, and animal handlers. Preexposure prophylaxis consists of three doses of intramuscular injections (deltoid area) of vaccine on Days 0, 3, and 21 or 28. A booster dose is needed to maintain a neutralizing antibody titer of 1:5 in high-risk people (researchers working with rabies vaccine, veterinarians) after testing at 6 months later.

Postexposure prophylaxis requires careful evaluation and judgment. Every year, more than 1 million people are bitten by animals in the United States, and approximately 25 000 receive postexposure rabies prophylaxis. Worldwide, more than 15 million people receive rabies vaccine after rabid animal bites (postexposure) that prevent thousands of death annually worldwide. The physician must consider (1) whether the individual came into physical contact with saliva or another substance likely to contain rabies virus; (2) whether there was significant wound or abrasion; (3) whether rabies is known or suspected in the animal species and area associated with the exposure; (4) whether the bite was provoked or unprovoked (ie, the circumstances surrounding the exposure); and (5) whether the animal is available for laboratory examination.

Any wild animal or ill, unvaccinated, or stray domestic animal involved in a possible rabies exposure, such as an unprovoked bite, should be captured and killed. The head should be sent immediately to an appropriate laboratory, usually at the state health department, to search for rabies antigen by immunofluorescence. If examination of the brain by this technique is negative for rabies virus, it can be assumed that the saliva contains no virus and that the exposed person requires no treatment. If the test is positive, the patient should be given postexposure prophylaxis. It should be noted that rodents and rabbits are not important vectors of rabies virus. There have been no rabies deaths in the United States when postexposure prophylaxis was given promptly after exposure.

Postexposure prophylaxis is based on immediate, thorough washing of the wound with soap and water (to kill the virus around the wound); passive immunization with antirabies hyperimmune globulin, including a portion instilled around the wound site (to neutralize the virus); and active immunization with antirabies vaccine on Days 0, 3, 7, and 14. For individuals who were previously immunized, the postexposure prophylaxis includes would cleansing with soap and water and rabies vaccination on Days 0 and 3 (hyperimmune globulin should not be given). Physicians should always seek the advice of the local health department when the question of rabies prophylaxis arises.