Revisiting Rabies

Emerg Med 39(8):30, 2007

By Heather Crooks Bruner, MD, and Francis L. Counselman, MD

Although most cases occur in developing countries, rabies is still a disease with significant morbidity and mortality in the United States. The authors discuss the rabies virus, patient evaluation, and potentially lifesaving post-exposure prophylaxis.

While human rabies is uncommon in the United States, the disease is quite prevalent among North American wildlife—in raccoons, skunks, foxes, and especially bats. Between 1990 and 2003, 27 of the 32 human cases of rabies acquired within the United States were associated with bats. Outside the United States, dogs remain a major reservoir of rabies, especially in Asia, Africa, and Latin America. People in China are not allowed to own more than one dog because of a rabies epidemic there.

There are an estimated 35,000 to 40,000 human rabies deaths each year worldwide, with the vast majority occurring in developing countries. Even in the United States, rabies still represents a disease with significant morbidity and mortality, which is best averted with the appropriate and timely administration of post-exposure prophylaxis (PEP) after a bite from a rabid animal. It has been estimated that approximately 35,000 patients receive PEP for possible rabies exposure each year in the United States. The challenge for the emergency physician is proper identification of high-risk exposures, allowing patients at risk to receive appropriate prophylaxis.

In this article, we will review the rabies virus and its pathogenicity, clinical features of infection, and evaluation of potential exposures. Key considerations and interventions in administering PEP will also
be discussed.

RABIES VIRUS

The virus responsible for causing rabies is a rhabdovirus of the genus Lyssavirus. It is introduced into the patient via the saliva of a rabid animal. Bites that break the skin have traditionally been the most common means of exposure. However, there have been reports of mucous membrane exposures, inhalation of aerosolized rabid bat feces, and transmission via organ transplantation.

Clinical rabies infection requires central nervous system (CNS) penetration. The rabies virus reaches the CNS by first gaining access to the peripheral nervous system via neuromuscular junction acetylcholine receptors at the site of the bite. The virus is then transported along these peripheral neurons to the CNS via retrograde axoplasmic flow at a rate of 12 to 100 mm per day.

Active CNS replication of the virus occurs primarily in the gray matter and is marked clinically by the characteristic behavioral changes of rabies and pathologically by pathognomonic eosinophilic inclusion bodies (Negri bodies) seen on post-mortem examination. Infectivity follows centrifugal spread from the CNS, with viral budding into the acinar lumen of the salivary glands.

The incubation period between exposure to the rabies virus and development of clinical symptoms varies greatly. Incubation periods of up to one year have been reported, but three-week to three-month periods are more typical. In general, bites on the head and neck have a shorter incubation period than those on the trunk or lower extremities.

CLINICAL FEATURES

The first symptoms of clinical rabies infection are nonspecific and often confused with a benign viral infection. Prodromal symptoms such as malaise, fever, chills, headache, nausea and vomiting, dyspnea, and cough are common. Behavioral changes are also typical; these include apprehension, anxiety, agitation, and depression. Pain, paresthesias, and weakness at or near the site of inoculation have been reported. Symptoms usually progress over a few days to one week.

Central nervous system involvement heralds the acute neurologic phase of the disease, which is “furious” in 80% of patients and “paralytic” in 20%. Furious refers to the hyperactivity, disorientation, hallucinations, and irritability that patients with this form of rabies exhibit. Fever and tachycardia are also common. Classic hydrophobia, caused by spasms of the pharynx and diaphragm with attempts to swallow liquids, is present in only about 50% of furious rabies patients. Paralytic rabies patients often experience an ascending paralysis, not unlike Guillain-Barré syndrome.

In both forms of rabies, the patient’s level of consciousness progressively declines. Coma and death generally occur within two to three weeks of initial symptom onset. Even with aggressive and intensive care, the disease is nearly uniformly fatal, with the majority of patients dying within three weeks from a variety of causes, including respiratory failure, cardiac arrhythmias and arrest, autonomic dysfunction, renal failure, and secondary bacterial infections. There is no treatment or cure; prevention is the key.

EVALUATING EXPOSURES

The outcome of a direct rabies exposure is determined by several variables, most of which are unknown to the treating physician at the time of evaluation. These include: the virus variant, dose of the inoculum, route and location of exposure, and patient factors, such as age and immune system status. The table below lists the relative risks of developing rabies in the absence of PEP after exposure to a rabid animal.

Examples of indirect exposures include contact with animal blood, feces, or urine, none of which have been reported to transmit rabies. Furthermore, the rabies virus is inactivated by desiccation and ultraviolet radiation. Dried animal secretions are considered noninfectious.

When evaluating a potential exposure to the rabies virus, the Centers for Disease Control and Prevention (CDC) recommends that clinicians consider the following three questions:
• Was the patient bitten?
• Did saliva or CNS material (such as brain tissue) contaminate an open wound or mucous
membrane?
• Was the animal a bat?

If the answer to all three questions is no, it is safe to assume an exposure has not occurred and no PEP is required. If the answer to any of the above is yes, an exposure is possible. Using the table below, you can then determine the appropriate action for a given exposure.

HIGH- AND LOW-RISK ANIMALS

In 2002, nearly 92% of reported cases of animal rabies in the United States were in wild animals. Generally speaking, if the animal is low-risk (for example, a domesticated dog, cat, or ferret) and available for quarantine, PEP can be avoided unless the animal demonstrates signs of clinical rabies within 10 days. Other animal bites that rarely require rabies PEP include those of squirrels, hamsters, guinea pigs, gerbils, rats, and mice. If the animal is high-risk, such as a raccoon, skunk, fox, or bat, and is available for euthanization and testing, PEP may be delayed pending the test results. Often, however, high-risk animals are not available for testing and therefore must be assumed to be rabid, which warrants immediate PEP.

Bat exposures deserve special consideration. The majority of human cases of rabies in the United States since 1980 have been associated with bat exposures. Interestingly, only two of those exposures involved a bat bite. A bat bite is often so small as to not be recalled, especially by a victim who may have been sleeping, intoxicated, or otherwise compromised at the time of the exposure or nonverbal on presentation. Physical examination at the time of presentation is also not reliable for detecting bat bites. For this reason, nearly all cases of direct contact between people and bats require prompt PEP. The CDC recommends initiating PEP immediately, even if the bat is available for testing. The vaccination series can be halted if the rabies testing on the bat proves negative.

There has never been a documented transmission of the rabies virus from a patient diagnosed with clinical rabies to a health care worker. Nevertheless, exposures among health care workers treating patients with rabies should be evaluated in much the same way as exposures from animals. A bite inflicted by the patient, penetration of the skin with contaminated sharps, or mucous membrane exposure to patient saliva or CNS material would be indications for PEP administration. Adherence to standard precautions and use of appropriate personal protective equipment, such as gloves, are prudent measures.

Persons who are at high risk for exposure to the rabies virus, such as animal control workers and veterinarians, may have received pre-exposure prophylaxis. While this would obviate the need for human rabies immune globulin (HRIG) administration on exposure, the need for further vaccination is still necessary. The dosing of vaccination for these patients is detailed in the table below.

POST-EXPOSURE PROPHYLAXIS

Adequate PEP begins first and foremost with prompt wound care. Washing the point of entry (for example, the bite mark or break in the skin) with soap and water has been shown in animal studies to markedly reduce the likelihood of the patient developing rabies after an exposure. Tetanus immunization status should be obtained, and a booster administered if it is not current. Indications for prophylactic antibiotics will depend on the species of animal, location and depth of the wound, and the patient’s immune status. Obviously, all clinically established infections must be treated with antibiotics. If it is determined that a high-risk rabies exposure has occurred, immunization should be initiated.

Immunization refers to the administration of agents that provide both passive and active immunity against the rabies virus. The first agent administered is HRIG, which is more commonly known by various trade names (such as BayRab and Imogram Rabies-HT). It is available in 2- and 10-ml vials for pediatric and adult use, respectively. Vials are standardized at 150 IU IgG/ml. Human rabies immune globulin provides a rapid, passive immunity that persists for only a short time (its half-life is approximately 21 days).

Active immunity is induced by the rabies vaccine, which leads to the production of endogenous rabies virus-neutralizing antibodies. This antibody response requires approximately 7 to 10 days to develop and usually persists for approximately two years.

The recommended dosage for HRIG is 20 IU/kg. As much of it as possible should be infiltrated aroundthe site of the bite (or bites); any remaining HRIG should be given intramuscularly at a site distant from the vaccine site. Unfortunately, many physicians still use the outdated 50:50 recommendation—that is, they administer half of the HRIG dose at the bite site, the other half elsewhere.

In the United States, there are three types of rabies vaccine available and multiple manufacturers of HRIG. Accepted vaccines include the human diploid cell vaccine (HDCV, the most commonly used), the rabies vaccine adsorbed (RVA), and the purified chick embryo cell vaccine (PCEC). The HDCV is available in both an intramuscular and an intradermal formulation; the RVA and PCEC are only offered in intramuscular formulations.

EFFICACY AND SAFETY

Although no randomized controlled trials regarding the efficacy of PEP exist, extensive field experience worldwide indicates that PEP (including wound treatment, passive immunization, and vaccination) is uniformly effective when done properly. If it is not carried out appropriately, the risk of rabies increases after exposure.

Adverse reactions to PEP are typically mild and do not prevent completion of the vaccination series. Local reactions, such as pain, swelling, and itching, are commonly reported. Systemic symptoms (headache, nausea, myalgias, abdominal pain) are much less common. There have been three case reports of Guillain-Barré-like neurologic symptoms that resolved within 12 weeks. There have been no reports of any viral transmission via HRIG.

The only contraindication to implementation of PEP is symptoms of clinical rabies. Because incubation periods of longer than one year have been reported in human rabies, the length of the delay between exposure and presentation for care does not preclude administration of PEP, provided that no clinical symptoms of rabies are present. Pregnancy and infancy are also not contraindications to PEP.

Corticosteroids, antimalarials, and other immunosuppressive drugs and diseases have been shown to interfere with the development of an adequate immune response to rabies vaccine, but they are not contraindications to PEP. Such patients will require antibody titer testing approximately two to four weeks after the series is completed to confirm an appropriate response. There have not been any reported cases of PEP failure due to HIV infection.

American citizens exposed to rabies abroad may receive PEP that differs from the regimens discussed here. Post-exposure prophylaxis failures have occurred abroad, although these appear to be attributable more to incorrect technique rather than vaccine failure. Failures to adequately cleanse the wound, to infiltrate the wound with HRIG, or administer the vaccine in the deltoid area are several cited mistakes made abroad.

Unpurified equine rabies immune globulin (ERIG) may be used in some developing countries, where purified ERIG or HRIG are not available. This form is associated with significantly higher risk of anaphylaxis.

COMMON CONCERN

Although human rabies is a rare clinical entity, its nearly uniformly fatal clinical course and its endemic nature in U.S. wildlife make it a relatively common concern for emergency physicians evaluating patients with animal bites. All such bites warrant thorough cleansing, a tetanus booster (if not current), and possible prophylactic antibiotic coverage. The safety and efficacy of HRIG and rabies vaccine in the United States make their early and appropriate use the most important tools in eradicating the devastating consequences of human rabies infection.

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