Rabies Virus

Since antiquity, rabies has been regarded as one of the most terrifying zoonotic diseases, especially in the context of virus transmission from man’s historic companion animal, the dog. One of the earliest potential suggestions of human rabies resulting from the bite of a dog is in the Eshnunna Code of Babylon, dating from the 23rd century B.C. (60). The saliva of rabid dogs was recognized as an infectious material centuries ago and was described using the Latin word "virus", meaning poison or slimy liquid (55). The history of rabies as a cause of human mortality is closely associated with the domestication of the dog, but it is also well established that rabies virus reservoirs occur in many sylvatic species, such as bats, foxes, mongoose, raccoons, and skunks (29).

In developed areas of the world, rabies is no longer a significant cause of human mortality, due in large part to control programs in free-ranging animals, widespread canine vaccination campaigns, and availability of safe and effective biologicals for human post-exposure prophylaxis. However, the disease remains an important threat in the developing world, causing an estimated 55,000 human deaths annually (64). The extrapolated public health costs associated with detection, prevention, and control of rabies in the United States exceed $300 million annually (64). The cost of such programs can be prohibitive in developing countries, whose limited public health infrastructure must contend with a variety of epidemic diseases. Thus, although human rabies is a preventable disease, economic considerations render it unpreventable in many parts of the world.

Virology

Rabies virus is classified taxonomically in the family Rhabdoviridae, genus Lyssavirus. The distinct bullet-shaped virion contains a single-stranded, nonsegmented, negative-sense RNA genome which encodes 5 structural proteins: the RNA-dependent RNA polymerase, nucleocapsid protein, phosphoprotein, matrix protein, and glycoprotein. The first 3 proteins are associated with the genomic RNA and together form the ribonucleoprotein core, whereas the matrix protein forms the inner aspect of the lipid envelope of the virion. Glycoprotein spikes cover the outer surface membrane and contain the epitopes against which virus neutralizing antibodies are produced (65). Monoclonal antibodies directed against both nucleocapsid and glycoprotein antigens have been developed and used to demonstrate that antigenically unique variants of rabies virus circulate in various geographic areas and are usually associated with a primary reservoir species of carnivore or bat (49, 52). Additional classification of rabies viruses into particular species or genotypes by genetic sequencing has permitted detailed analyses of enzootic maintenance cycles of specific virus variants, as well as provided information regarding variability of the virus itself (51).

Epidemiology

The epidemiology of human rabies is ultimately linked to cycles of virus transmission in animals. Although rabies virus can potentially infect any mammal, the vast majority of human rabies cases worldwide are associated with transmission from domestic dogs. The canine variant has been eliminated from the United States (8); therefore rabies is maintained only in wild animal reservoirs. Eight genetically distinct variants are recognized in terrestrial mammals within broad geographic regions. These include variants associated with raccoons (Procyon lotor) in the eastern United States; red (Vulpes vulpes) and Arctic (Alopex lagopus) foxes in Alaska; gray foxes (Urocyon cinereoargenteus) in Arizona, New Mexico, and Texas; and skunks (primarily Mephitis mephitis) in California, the north central states, and the south central states. Multiple independent reservoirs for rabies virus also exist in populations of insectivorous bats. Cases of rabies have been reported in more than 30 different species of bats from all states (except Hawaii, which is “rabies-free”).

Bat variants are increasingly implicated in human rabies cases in the United States. Prior to 1990, the majority of human rabies cases were associated with terrestrial mammals. However, from 1990 to 2008, infection with variants associated with insectivorous bats accounted for 39 (72%) of the 54 human cases diagnosed in the United States (4 of the 39 patients received organ or tissue transplants from a donor with unrecognized rabies). Foreign canine rabies virus variants accounted for 12 (22%) of the cases (Centers for Disease Control and Prevention [CDC], unpublished data). Approximately 6,500-7,000 cases of rabies in animals have been reported annually in the United States in recent years (8-10). The proportion of bats among these cases has risen significantly in the past decade, from 11.3% in 1997 (37) to 27.2% in 2007 (10). This, however, reflects increased submissions and testing of bats due to greater awareness of the risk of bat rabies rather than an actual overall increase. Approximately 6.5% of bats tested by health departments are found to be rabid (10), although reviews of studies involving randomly captured bats have found only about 1% to be rabid (42).

In summary, current epidemiologic patterns of human and animal rabies in the United States show that the majority of rabies (more than 90% of reported cases) occurs in wild animals; bat variants are disproportionately associated with indigenously acquired human rabies cases; and most non-bat-associated human cases can be attributed to infections acquired in areas with enzootic canine rabies outside of the United States.

Clinical Manifestations 

The clinical presentation of rabies is often reported categorically as either encephalitic (furious) or paralytic (dumb). The former indicates derangement of cerebral functions while the latter describes impairment of spinal cord and peripheral nerve functions. However, the clinical distinction between these forms is often unclear, as patients with rabies can exhibit signs suggestive of either category. Furthermore, some patients present with atypical signs of rabies. The clinical presentation of rabies may rely more on genetic or host factors, such as the inflammatory response (39), than on the reservoir species, route of infection, or specific viral variant.

Despite variations in clinical presentation, human rabies infection generally progresses through a series of 5 general clinical phases: incubation, prodrome, acute neurologic period, coma, and, almost invariably, death. The length of the incubation period is quite variable and depends upon several factors, such as the anatomical site of virus inoculation (and its relative innervation), the quantity of virus introduced, and the age and immune status of the patient (31). Incubation periods as short as 5 days and as long as several years have been documented (27), but usually range from 30-90 days. In cases with either extremely short or extremely long incubation periods, the possibility of unknown or unrecognized exposures cannot be easily excluded. The prodromal phase of illness may last for up to 10 days, and is characterized by nonspecific constitutional, respiratory, or gastrointestinal symptoms, such as fever, chills, malaise, cough, headache, anxiety, nausea, and vomiting. Local paresthesia, pruritus, or pain at the site of virus inoculation is often present, indicating viral presence in the dorsal root ganglia and central nervous system (CNS). These signs are not pathognomonic for rabies but are important clues that may allow for an early diagnosis. The neurologic phase is characterized by disturbances in CNS function and typically lasts 2 to 10 days. Clinical manifestations include extreme agitation, restlessness, hyperactivity, and signs of autonomic instability, such as hypersalivation, lacrimation, sweating, and tachycardia. Hydrophobia, aerophobia, and dysphagia are common presentations, resulting from exaggerated respiratory tract irritant reflexes. These signs may be precipitated by the mere proximity or mention of water or the threat of being touched by a draft of air, especially on the face. Clinical deterioration continues rapidly until CNS dysfunction results in either generalized paralysis and coma or sudden death due to respiratory or cardiac arrest. Death follows coma within hours to days, usually resulting from complications of hypoxemia, cardiac arrhythmias, cerebral edema, or hypotension (31, 47). Death usually occurs within 14 days of onset of symptoms, although critical care measures may prolong the course of illness.

Approximately 20% of human rabies patients present with prolonged ascending paralysis, similar to Guillain-Barre syndrome (21, 33, 34). In contrast to the hyperactive presentation, the patient’s mental status remains intact until much later in the clinical course, and the average period of survival is longer. However, the end result is the same as the patient gradually deteriorates into disorientation, stupor, coma, and finally, death. No definitive epidemiologic or molecular differences have been described among human rabies patients with this paralytic presentation.

The literature documents only 6 instances of recovery from clinical rabies, and 5 of these patients received either pre- or post-exposure vaccination prior to the onset of illness (reviewed by Jackson [34]). It has been suggested that some of these individuals may have experienced postvaccinal encephalomyelitis rather than rabies (31). Only one of these 5 patients made a complete recovery. A 6-year-old boy, who had been bitten by a bat, developed rabies after post-exposure vaccination with duck embryo vaccine and subsequently recovered with only supportive care (28). There is a single documented survivor of clinical rabies who did not receive rabies biologicals prior to symptom onset. A 15-year-old girl, who had been bitten by a bat and did not receive post-exposure prophylaxis, developed encephalitic rabies and was treated with therapeutic coma and antiviral agents (62). These patients were unusual in that they had high neutralizing antibody titers in both serum and cerebrospinal fluid (CSF) early in the course of disease. A recent database search concluded that survival appears to be related to early appearance of neutralizing antibodies in serum and CSF (58).

Laboratory Diagnosis 

The vast majority of human rabies cases reported to the World Health Organization (WHO) are diagnosed solely on the basis of clinical presentation. Common differentials include herpes virus and arboviral encephalitides, Guillain-Barre syndrome, tetanus, poliomyelitis, delirium tremens, psychosis, pharyngitis, cerebrovascular accident, and postvaccinal encephalomyelitis. Differentiating these conditions from rabies is critical in focusing treatment efforts and minimizing potential rabies virus exposures among health care personnel.

Of the 54 cases of human rabies reported in the United States from 1980 to 2008, only 36 (67%) were diagnosed prior to death (CDC, unpublished data), compared with 28 of 38 cases (74%) from 1960 to 1979 (1). The relative rarity of the disease in humans in the United States leads to a low level of suspicion of rabies by medical providers. Furthermore, a majority of indigenous human rabies cases in recent years have had no clear documented history of animal bite or other event typically associated with rabies virus transmission. A history of animal contact relevant to a rabies exposure in these cases is either not remembered by the patient or attending friends and family members or is not elicited by medical providers. This has coincided with the relative increase in bat-associated cases, indicating that encounters with bats may be unnoticed, forgotten, or disregarded as insignificant. A recent history of travel to, or emigration from, an area where canine rabies is endemic is also important information which may help providers reach a differential diagnosis of rabies. Careful attention to these details early in the clinical course may result in earlier rabies diagnoses and a reduction in the number of post-exposure prophylaxis regimens administered to medical personnel. Any patient who presents with severe, progressive encephalitis of unknown etiology should be considered a potential rabies case, even in the absence of recognized exposure. A review of 32 cases of human rabies diagnosed in the United States from 1980 to 1996 found that rabies was included in the differential diagnosis for only 6 (19%) of the case patients at the time of hospital admission (45). The presenting diagnoses for recent human rabies cases have included atypical neuropathy, bowel obstruction, carpal tunnel syndrome, myocardial ischemia (12), muscle strain (13), drug reaction or withdrawal syndrome (14), pharyngitis (15), aspiration pneumonia and sepsis (17), and idiopathic transverse myelitis (18).

Once the possibility of rabies is considered, laboratory confirmation may be established via standard serologic, antigen detection, virus isolation, or reverse transcription-polymerase chain reaction methodologies (50). There are no laboratory tests available to diagnose rabies prior to onset of clinical illness. Aspects of rabies pathogenesis may limit the potential for design and success of antemortem tests, so a battery of diagnostic tests should be performed to confirm the diagnosis. For antemortem rule-out of rabies, the CDC recommends diagnostic testing of 4 patient samples: saliva, serum, CSF, and nuchal biopsy (taken from the posterior region, or “nape”, of the neck at the hairline).

Serology

Two different tests are used routinely to detect anti-rabies virus antibody in serum or CSF. The rapid fluorescent focus inhibition test measures neutralizing antibody reactive with the rabies virus glycoprotein. An antibody titer is defined by the reciprocal of the sample dilution that completely neutralizes the challenge virus. An indirect fluorescent antibody test using patient serum or CSF is also used to detect antibody (both IgM and IgG) binding to the rabies virus ribonucleoprotein in infected cell cultures. Presence of antibody in serum is considered diagnostic if no vaccine or rabies immune globulin has been administered to the patient, whereas antibody in CSF is diagnostic of rabies regardless of immunization history. Serum samples taken very early in the clinical course may not be useful for diagnosis except as a baseline for subsequent samples, and serial testing is recommended while a rabies diagnosis is being entertained.

Virus Isolation

Virus may be detected by adding suspensions of brain or saliva samples to mouse neuroblastoma cells. The cells are cultured for 24 and 48 hours and then examined by the direct fluorescent antibody (DFA) test for evidence of infection with rabies virus. Intracerebral inoculation of suckling or weanling mice is another method to detect the presence of infectious virus in samples.

Antigen Detection

Detection of rabies virus antigen is performed by DFA testing of serial frozen sections of nuchal biopsies. Touch impressions of corneal epithelial cells or a brain biopsy may also be used for antigen detection. For optimal postmortem diagnosis of rabies, DFA tests should be performed on samples of the hippocampus, cerebellum, and medulla.

RNA Detection

Nucleic acids are extracted from samples of undiluted saliva, nuchal biopsies, and fresh or paraffin-embedded fixed samples of brain. Reverse transcription of RNA is followed by cDNA amplification by the polymerase chain reaction with rabies-specific oligonucleotide primers. This method has the advantage of obtaining DNA fragments which can be sequenced and analyzed using databases of known rabies virus variants, although the specialized equipment and expense of reagents may limit use of this technique to research or reference laboratories.

Pathogenesis

The pathogenesis of rabies remains incompletely understood. Neurotropism, neuroinvasiveness, and neuronal dysfunction are the hallmarks of rabies virus infection (23). After virus inoculation, a region of the rabies virus glycoprotein attaches to the plasma membrane of a host cell. Putative receptors include the nicotinic acetylcholine receptor, the neural cell adhesion molecule, and the p75 neurotrophin receptor (38). The virus may remain at the inoculation site for a prolonged period (5), perhaps replicating in local skeletal muscle (44) prior to entering peripheral nerves through unmyelinated motor and sensory axon terminals at the neuromuscular junction. Long-term retention of rabies virus within striated muscle fibers and fibrocytes has been suggested as a mechanism for the longer incubation periods that have been observed (20). However, direct viral entry into the peripheral nervous system without prior local replication has been observed in an experimental infection using a laboratory mouse model (48). After entering the nervous system, the virus is sequestered from the immune system, and the progression of infection is not easily inhibited by passive or active immunization. The virus then spreads by retrograde fast axonal transport until it reaches the CNS at the level of the spinal ganglia. At this stage, the first specific symptoms of disease, such as pain or paresthesia at the inoculation site, may be evident. Once in the CNS, the virus disseminates rapidly, leading to development of severe, progressive encephalitis. This is followed by centrifugal spread of virus along the peripheral nerves to the salivary glands, cornea, skin, and many other tissues. Infection of the acinar cells of the salivary glands leads to shedding of virus in saliva (19).

SUSCEPTIBILITY IN VITRO AND IN VIVO

There is a paucity of data demonstrating rabies virus susceptibility to antiviral agents either in vitro or in vivo. Ribavirin is a broad-spectrum antiviral with activity against RNA viruses and in vitro activity against rabies virus, but it has not proven beneficial in treatment of rabies (11, 57). Ketamine is a noncompetitive antagonist of exitotoxic N-methyl-D-aspartate (NMDA) receptors, and, at high concentrations in vitro, interferes with the replication of rabies virus by inhibiting transcription. After inoculation of rabies virus into the neostriatum of rats, high doses of ketamine led to reduced infection in multiple brain regions (40). However, more recent studies of ketamine in mice have failed to show any obvious benefit (59). Amantadine is also an NMDA antagonist with activity against negative-sense RNA viruses, but, as with other candidates, it has not been proven useful in the treatment of clinical rabies (54).

ANTIVIRAL THERAPY

There is no specific chemotherapy for clinical rabies. Therapy with interferon or antiviral drugs, such as ribavirin, vidarabine, adenosine arabinoside, and inosine pranobex, has been unsuccessful (31, 35). Similarly, vaccine and rabies immune globulin administration, initiated after the onset of clinical disease, have been ineffective (25) or have induced complications (32). A review of human rabies cases in the United States (45) showed that patients receiving antiviral therapy had a median duration of illness of 19 days (range, 7 to 28 days). This was not significantly different from those not receiving antiviral therapy (median, 15.5 days; range, 7 to 32 days). Among patients given rabies immune globulin during the course of illness, the median duration was also 19 days (range, 11 to 42 days). Combination therapy is considered more likely to be successful than treatment with any single agent (35). The protocol used in the treatment of the single unvaccinated survivor of rabies, known as the Milwaukee protocol, included therapeutic coma induction with ketamine, benzodiazepines, and barbiturates, along with antiviral drugs ribavirin and amantadine (62), although ribavirin is no longer recommended by the treatment team due to potential adverse effects (41). A number of attempts have been made to repeat the Milwaukee protocol (all with some modifications) in rabies patients in several countries, thus far without proven success, but this outcome is expected to change.

ADJUNCTIVE THERAPY 

Attempts at treatment are costly and, other than in the exceptional cases previously noted, only prolong the progression of the disease. Treatment is primarily aimed at maintaining neuroendocrine, cardiovascular, and respiratory function while the natural host immunological response develops to clear the virus. The most important clinical complications appear to be hypoxia, hypotension, cerebral edema, increased intracranial pressure, fluid imbalance, and cardiac arrhythmias (34, 47). Experimental therapeutics have included immunosuppressive drugs to lessen the degree of myocardtis resulting from T-cell response; competitive antagonists (e.g. ganglioside preparations) to inhibit excitotoxicity; oligonucleotide therapeutics to suppress viral genes; and cellular administration of polyclonal or monoclonal antibodies against internal viral proteins (31). These experimental treatments have all been unsuccessful to date.

ENDPOINTS FOR MONITORING THERAPY 

Recovery of neurological function in the unvaccinated rabies survivor was associated with a rapid increase in CSF neutralizing antibody. The Milwaukee protocol therefore recommends tapering sedation when antibody titers in the CSF increase dramatically (41). Rabies virus pathogenesis may falsely mimic brainstem death, complicating the use of conventional criteria to determine the presence of irreversible brain damage (41). One patient showed no neurologic recovery after withdrawal of sedation, despite markedly decreased rabies virus in the peripheral tissues and preserved brain perfusion. Histopathology eventually revealed virtually complete loss of cortical neurons (17).

VACCINES 

General

Although the case fatality rate of rabies approaches 100%, the disease is completely preventable in humans when exposures are recognized and appropriate and timely post-exposure prophylaxis (consisting of wound care, rabies immune globulin, and vaccine) is administered. Rabies vaccines induce an active immune response that depends on the production of neutralizing antibodies. This antibody response requires approximately 7 to10 days to develop and usually persists for years. Concomitant with vaccine, rabies immune globulin provides a rapid, temporary passive immunity while the active antibody response develops.

The first vaccine against rabies was developed by Louis Pasteur in the late 1880s. It consisted of a modified-live virus strain that was developed by serial passage in rabbit spinal cords. Modifications of this original nerve tissue vaccine were introduced during the next 50 years, but problems with low immunogenicity and frequent postvaccinal neurologic complications, such as encephalomyelitis and peripheral neuropathy, were encountered (53, 60). These Semple and Fermi-type animal nerve tissue vaccines are still used in some areas because they are inexpensive and relatively easy to produce. The late 1950s brought the development of 2 new vaccines (suckling mouse brain vaccine and duck embryo vaccine) that were free of the myelin basic proteins believed to be responsible for the immune-mediated neurologic complications associated with nerve tissue vaccines. The duck embryo rabies vaccine represented a significant improvement in that it was the first non-nervous tissue vaccine. It was used in the United States from 1958 to 1980, though low immunologic potency necessitated 14 to 21 daily injections, and adverse reactions were relatively common (46, 56).

The successful adaptation of rabies virus to human diploid cell culture led to the revolutionary introduction of a safe and potent rabies vaccine by workers at the Wistar Institute (36). The efficacy of the human diploid cell vaccine  along with administration of equine rabies immune globulin was demonstrated in 1976 among 45 persons severely bitten by rabid dogs and wolves in Iran. All developed rabies virus-neutralizing antibodies and none succumbed to the disease (4). Besides human diploid cell vaccine, one other cell culture vaccine, purified chick embryo cell vaccine, is currently licensed and available in the United States for pre- and post-exposure rabies prophylaxis. A purified Vero cell rabies vaccine (PVRV), which uses continuous cell lines for propagation of virus, is widely used in Europe and developing countries but is not licensed for use in North America. Only high quality cell culture vaccines manufactured according to WHO standards (63) are licensed for human use in industrialized countries, whereas in developing countries (where the vast majority of worldwide rabies exposures occur) either nerve tissue or lower quality cell culture vaccines are commonly used. The WHO has strongly recommended discontinuation of the use of these nerve tissue products in favor of modern cell culture vaccines (64).

Indications

Modern rabies post-exposure prophylaxis (post-exposure prophylaxis), consisting of immediate wound care and timely administration of rabies immune globulin and cell culture vaccine, is essentially 100% effective. Most human rabies fatalities in the developed world occur in individuals who fail to seek medical treatment, usually due to ignorance of the risk or a lack of recognition of an exposure.

In deciding whether to administer post-exposure prophylaxis to a person who may have been exposed to rabies, a physician should first determine whether an exposure indeed occurred and then assess the probability that the animal involved in the exposure was rabid. Rabies can be transmitted only when the virus is introduced into open cuts or wounds in skin or onto mucous membranes. The likelihood of rabies infection varies with the nature and extent of exposure. Two categories of exposure (bite and nonbite) are considered (Table 1). Any penetration of the skin by teeth constitutes a bite exposure. Bites to the face and hands carry the highest risk, but the site of the bite should not influence the decision to begin post-exposure prophylaxis. Open wounds or mucous membranes contaminated with saliva or nervous tissue from a rabid animal constitute nonbite exposures and present an inherently lower risk than do bite exposures. Other contact such as petting a rabid animal or contact with the blood, urine, or feces of a rabid animal does not constitute an exposure and is not an indication for post-exposure prophylaxis (16).

Guidelines for administration of post-exposure prophylaxis to persons potentially exposed to rabies by either domestic or wild animals have been established (Table 1), but the decision itself must take into account the circumstances surrounding the bite, the disposition of the animal, and the epidemiology of rabies in the area. In the United States, a healthy domestic dog, cat, or ferret (regardless of rabies vaccination status) that bites a person should be confined and observed for 10 days in lieu of immediate post-exposure prophylaxis administration, since the pathogenesis, clinical signs of rabies, and the viral shedding period are well established for these animals. If the dog, cat, or ferret is rabid at the time of an exposure, the animal will begin to show clinical signs during the 10 day period and should be euthanized immediately and tested for rabies. Once the animal is diagnosed as rabid, then post-exposure prophylaxis is administered to exposed persons. On the other hand, since the incubation period, excretion dynamics, and clinical signs of rabies cannot be reliably interpreted in wildlife, post-exposure prophylaxis is recommended for humans with a bite, scratch, or mucous membrane exposure to any wild mammal (especially a reservoir species) unless the animal tests negative for rabies. Small rodents and lagomorphs are rarely found to be rabid, and exposures to such animals constitute a very low risk and have never been implicated in a case of human rabies. Large rodents, such as woodchucks and beavers, in areas of the United States affected by raccoon rabies present a somewhat higher risk, due to the opportunity for spillover infection from rabid raccoons. All species of livestock are susceptible to infection but are infrequently found to be rabid. Cattle and horses are the most commonly reported rabid livestock, and in many cases these animals have a history of exposure to a reservoir species, such as a raccoon, skunk, or fox. As such, consideration should be given to vaccinating livestock that are particularly valuable or that might have frequent contact with humans (such as in petting zoos), and risk assessments for humans exposed to livestock under these circumstances should take vaccination status into account.

Indirect human exposures, such as caring for wounds inflicted by a wild animal to a pet dog or cat, do not constitute a high risk of exposure to rabies and have never resulted in a documented human fatality. Rabies virus does not persist in the environment, and is inactivated by extreme pH as well as by desiccation, ultraviolet radiation, trypsin, beta-propiolactone, ether, and detergents (27). In unclear cases of potential exposure, the state or local health department should be consulted to assist in the decision whether or not to recommend post-exposure prophylaxis to an individual. As noted, bats are increasingly implicated as a significant reservoir for variants of rabies virus transmitted to humans in the United States, but a history of a bite from a bat has been established in only a few cases. Cases with an established history of bat contact include various scenarios: a bite, direct contact with bats with opportunity to be bitten, and possible direct contact with a bat (43). Recent epidemiologic data suggest that transmission of rabies virus may occur from minor or seemingly insignificant bites from bats. The limited injury inflicted by a bat bite (in contrast to lesions caused by carnivores) and an often inaccurate recall of the exact exposure history may limit the ability of health care providers to determine the risk of rabies resulting from an encounter with a bat. In all instances of potential human exposures involving bats, the bat in question should be safely collected, if possible, and submitted for rabies diagnosis. post-exposure prophylaxis is recommended for all persons with bite, scratch or mucous membrane exposure to a bat, unless the bat tests negative for rabies. Moreover, post-exposure prophylaxis may be appropriate even in the absence of demonstrable bite, scratch or mucous membrane exposure in situations in which there is reasonable probability that such exposure may have occurred (e.g. a bat is found in the room with an unattended child or incapacitated adult). Suitable risk assessments and adherence to the Advisory Committee on Immunization Practices (ACIP) guidelines should maximize a provider's ability to respond to situations where accurate exposure histories may not always be obtainable, while still minimizing inappropriate post-exposure prophylaxis (16).

Doses and Schedule

The post-exposure prophylaxis regimen recommended by the ACIP includes immediate local wound care (soap and water and irrigation with a virucidal agent such as povidone-iodine solution) along with administration of one dose of rabies immune globulin on day 0 and a series of 5 1.0-mL doses of cell-culture vaccine on days 0, 3, 7, 14, and 28 (the Essen regimen) (Table 2). The vaccine is administered intramuscularly (IM) in the deltoid, or, alternately, in the upper thigh of young children. Generally an immunization series should be initiated and completed with one vaccine product, although there is no evidence of any change in efficacy or frequency of adverse reactions when the series is completed with a different vaccine. If anatomically feasible, the full dose of rabies immune globulin (20 IU per kg body weight for human rabies immune globulin; 40 IU per kg body weight for equine rabies immune globulin) should be infiltrated into and around the site of the wound. If this is not possible, the remainder of the dose should be administered IM at a site distant from the vaccine administration site. The rabies immune globulin should never be administered in the same syringe or at the same anatomical site as vaccine. If administration is delayed, rabies immune globulin can be given up to day 7 following the initial vaccine dose. After day 7, it is contraindicated due to the potential for interference with the active immune response. This regimen is recommended for all types of potential rabies exposure (16). Pregnancy, infancy, or previous adverse reactions are not contraindications for post-exposure prophylaxis (16, 22). The WHO has approved the use of several modified post-exposure prophylaxis regimens designed to reduce the cost of post-exposure prophylaxis in developing nations. These are the Zagreb (2-1-1) IM regimen, the Thai Red Cross intradermal (ID) regimen, and the 8-site intradermal regimen (63). Intradermal regimens conserve vaccine by employing 0.1-mL doses, but there are no approved formulations for the intradermal route in the United States at the present time.

Strict adherence to recommended post-exposure prophylaxis protocols is critical. Although there have been no post-exposure prophylaxis failures in the United States since human diploid cell vaccine was licensed in 1980, a small number of cases of rabies have occurred in other countries in persons who had received post-exposure prophylaxis. In most of these cases, there was some deviation from the recommended protocol (e.g., no local wound treatment, inappropriate rabies immune globulin administration, or vaccine administration in the gluteal area rather than the deltoid) (61).

Pre-exposure prophylaxis (Table 3) is recommended for persons whose occupational or vocational pursuits lead to increased risk of frequent or unrecognized exposures to rabies. These include veterinarians, animal handlers, rabies laboratory workers, and certain persons spending more than 30 days in countries where canine rabies is endemic, based upon their activities. The pre-exposure prophylaxis regimen approved in the United States consists of a series of 3 1.0-mL doses of vaccine administered IM in the deltoid on days 0, 7, and 21 or 28. A single booster dose is recommended if the serum antibody titer falls below 1:5 by rapid fluorescent focus inhibition test and continuous or frequent risk of exposure to rabies remains an issue (Table 3). Pre-exposure vaccination does not eliminate the need for wound treatment and vaccination after exposure; however, the requirement for rabies immune globulin administration is obviated and the post-exposure series is reduced to 2 doses of vaccine, on days 0 and 3 (Table 2).

Immunosuppressed individuals should have their virus neutralizing antibody titers checked 7 to 14 days after completing either pre-exposure prophylaxis or post-exposure prophylaxis (16). Another important consideration is the deleterious effect of concurrent administration of antimalarial drugs (e.g. chloroquine phosphate) on the antibody response after vaccination, especially among individuals who receive the regimen via the intradermal route (6).

Adverse Effects

Reactions after vaccination with cell culture vaccines are much less serious and common than with previously available vaccines. Nevertheless, reported adverse reactions among vaccine recipients include local pain, redness, swelling, itching, and induration. Systemic effects such as nausea, fever, vomiting, malaise, and lymphadenopathy have also been noted. Local reactions occurred among 19% to 74% of vaccinees, while systemic effects were reported in 5% to 40% (2). Mild local and systemic reactions are treated symptomatically, if at all, and do not justify discontinuation of the post-exposure prophylaxis regimen.

There have been at least 4 reports of a Guillain-Barre-like neurologic syndrome temporally associated with human diploid cell vaccine administration, although a definitive causal relationship was not established, and all affected individuals recovered without sequelae (7). Also, an immune complex-like reaction has been reported among approximately 6% of persons receiving booster doses of human diploid cell vaccine. These patients begin to experience generalized urticaria, arthralgia, angioedema, nausea and vomiting 2 to 21 days after administration of the booster dose of vaccine (24). This reaction appears to be associated with the development of IgE antibodies to beta-propiolactone-altered human serum albumin in the vaccine (3). In no cases were these reported illnesses life-threatening.

When a person with a history of serious hypersensitivity to rabies vaccine must be revaccinated, antihistamines may be given and epinephrine should be readily available to counteract potential anaphylactic reactions. These individuals should receive vaccination in a location that permits careful observation and monitoring following vaccine administration, such as an emergency room. In general, corticosteroids should not be administered to treat adverse effects of vaccination. Steroids have been reported to increase rabies mortality among experimentally-infected animals and to decrease immune response to vaccination (26).

PREVENTION OR INFECTION CONTROL MEASURES

It is important to institute appropriate barrier precautions to protect medical personnel from contact with a patient’s saliva, CSF, tears, and centrifuged urine (30). Human rabies patients do not pose any greater infection risk to healthcare personnel than do patients with more common infections (16). Standard precautions as outlined by the Hospital Infection Control Practices Advisory Committee should be followed. Personnel should wear gowns, goggles, masks, and gloves, particularly during intubation and suctioning. Post-exposure prophylaxis is indicated only if a person has been bitten by the patient or when saliva or other potentially infectious material has contaminated an open wound or mucous membrane. To date, there has been no documented transmission of rabies virus to a health care worker. Despite the low risk, an average of about 50 (and up to 179) persons have received rabies post-exposure prophylaxis for possible exposure to infectious material from every human rabies patient in the United States since 1980 (CDC, unpublished data).

COMMENTS

Rabies should be considered in any patient with rapidly progressive encephalitis. The initial presentations of rabies can be diverse and a history of animal contact is rarely obtained. Because the immune response to rabies may not occur until late in the disease, if rabies is suspected, antemortem samples for testing should include a nuchal skin biopsy, saliva, serum, and CSF. Although modern vaccines and rabies immune globulin have revolutionized rabies post-exposure prophylaxis, issues of cost and availability continue to be matters of tremendous concern and impact. Clearly, the need for human rabies vaccines and rabies immune globulin replacements that are potent, safe, and inexpensive is a priority throughout the world. Increased efforts to eliminate rabies in animal reservoirs remain the most important strategy to prevent human rabies. These goals are best attained by continued basic and applied studies of rabies virus pathobiology and immunoprotective mediators specific for rabies virus in both human and animal populations.

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Table 1. Rabies post-exposure prophylaxis recommendations*

Animal species	Evaluation and disposition of animal	Post-exposure prophylaxis  (PEP) recommendations
Dog, cat, ferret	Apparently healthy and available for observation	No PEP unless animal develops clinical signs within 10 days and tests positive for rabies†
	Rabid or suspected rabid	Immediate PEP
	Unknown (e.g., escaped)	Consult public health officials
Skunk, raccoon, fox other wild carnivore; bat	Regarded as rabid unless animal tests negative‡	Consider immediate PEP
Small rodent (mouse, squirrel), lagomorph (rabbit, hare)	Consider individually	Almost never require PEP
Livestock, large rodent (woodchuck, beaver); other mammal	Consider individually	Consult public health officials

*Adapted from Recommendations of the Advisory Committee on Immunization Practices: Human rabies prevention—United States, 2008.

†PEP should be withheld until animal tests positive unless test results are likely to be delayed.

‡Wild animals should not be held for observation; rather, they should be euthanized and tested for rabies virus infection as soon as possible

after a human exposure. PEP can be discontinued if test results are negative.

Table 2. Rabies post-exposure prophylaxis schedule*

Vaccination status	Treatment	Regimen
Not previously vaccinated	Local wound cleansing	Immediately cleanse all wounds with soap and water and irrigation with a virucidal agent such as povidone-iodine solution.
	RIG	Administer 20 IU/kg body weight on day 0†. If anatomically feasible, the full dose should be infiltrated around the wounds(s). Any remaining volume should be administered IM at a site distant from vaccine administration. RIG should not be administered in the same syringe as vaccine. Because RIG might partially suppress the active antibody response, no more than the recommended dose should be given.
	Vaccine	HDCV or PCECV: 1.0 mL, IM (deltoid‡) days 0†, 3, 7, 14, and 28.
Previously vaccinated§	Local wound cleansing	Immediately cleanse all wounds with soap and water and irrigation with a virucidal agent such as povidone-iodine solution.
	RIG	RIG should not be administered.
	Vaccine	HDCV or PCECV: 1.0 mL IM (deltoid‡) on days 0† and 3.

*Adapted from Recommendations of the Advisory Committee on Immunization Practices: Human rabies prevention—United States, 2008.

†Day 0 is the first day of vaccine administration, not necessarily the day of exposure.

‡Vaccine may be administered in the lateral thigh in young children; vaccine should never be administered in the gluteal area.

§Any person with a history of pre-exposure vaccination or PEP with approved vaccine or vaccination with any other type of rabies vaccine

and documented neutralizing antibody response.

Abbreviations: HDCV – human diploid cell vaccine; PCECV – purified chick embryo cell vaccine; RIG – rabies immune globulin

Table 3. Rabies pre-exposure prophylaxis schedule*

Type of Vaccination	Regimen
Primary	HDCV or PCECV: 1.0 mL IM (deltoid) on days 0†, 7, and 21 or 28
Booster	HDCV or PCECV: 1.0 mL IM (deltoid) on day 0† only

*Adapted from Recommendations of the Advisory Committee on Immunization Practices: Human rabies prevention—United States, 2008.

†Day 0 is the day the first dose of vaccine is administered.

Abbreviations: HDCV – human diploid cell vaccine; PCECV – purified chick embryo cell vaccine

GUIDED MEDLINE SEARCH FOR

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Review articles

Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies.  MMWR, March 2010.

Susan E. Manning, et al. CDC Human Rabies Prevention United States 2008. CDC 2008.

Halpin K, Hyatt AD, Plowright RK, Epstein JH, Daszak P, Field HE, Wang L, Daniels PW, and the Henipavirus Ecology Research Group.  Emerging Viruses: Coming in on a Wrinkled Wing and a Prayer.  Clin Infect Dis 2007;44:711-717. 

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Ullman A.  Pasteur-Koch: Distinctive Ways of Thinking about Infectious Diseases.  Microbe 2007;2(8):383-387.

Young G. The Face of Evil. Annals of Internal Medicine. 133:558, October 3, 2000.

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