Perspective

Rabies in humans remains rare in the United States. Only 36 cases were reported in the United States in the 20 years from 1980 to 2000,^1,2 but rabies exposures in the United States require that approximately 40,000 people receive postexposure prophylaxis annually.³ Human rabies cases in the United States continue to occur, with 2 cases detected in 2008, 4 in 2009, and 1 in 2010.⁴ International travelers are at increased risk of exposure to rabies and may return to the United States to receive postexposure prophylaxis or rabies treatment. Rabies is a fatal disease.^1,2,5,6 Only 6 people are known to have survived the disease.^7–13 The low rate of occurrence of the disease challenges physicians to consider this in the differential diagnosis of encephalitides.

Postexposure prophylaxis, if started before clinical signs of rabies develop, is highly effective. With strict adherence to protocol, including wound care, passive immunization, and vaccination with a cell culture vaccine, postexposure prophylaxis prevents rabies.^2,14–16 Emergency physicians (EPs) should know when to begin rabies postexposure prophylaxis, when to delay it, and when postexposure prophylaxis is not indicated, and they should also know state and local resources for rabies information.

Anatomy

Rabies is transmitted when saliva or neural tissue from an infected host contacts open wounds or mucous membranes of a recipient. This transmission can occur through bites, aerosolized tissue, or tissue transplantation. Rabies virus is not transmitted by blood, feces, or urine. Rabies is not transmitted across intact skin.²

Once the virus is in a new host, it performs one of two actions. Some virus replicates at the site of the bite in non-nerve tissue. The virus then enters peripheral nerves and travels to the central nervous system (CNS). Some virus does not replicate at the site, but rather immediately enters the peripheral motor and sensory nerves for transport to the CNS. During this time, the virus is in an eclipse phase, and it is difficult to detect with diagnostic tests.¹⁷ The virus travels at speeds of 15 to 100 mm/day by retrograde axoplasmic flow.⁶ When the virus enters the CNS, the incubation time ends. Incubation times range from 2 weeks to several years, and the average is 2 to 3 months.^6,17 Once in the CNS, the virus replicates and spreads by cell-to-cell transfer. The virus then travels by anterograde axoplasmic flow to nervous and non-nervous tissue. At the onset of clinical symptoms, the virus is disseminated throughout the body.

Pathophysiology

Rabies is caused by a negative-stranded RNA virus that belongs to the Lyssavirus family. The virus envelope fuses to the host cell membrane, and the virion penetrates the cell, where it replicates and buds new virus.

The virus causes inflammation in the CNS, both encephalitis and myelitis. Perivascular lymphocytic infiltration occurs with lymphocytes, polymorphonuclear leukocytes, and plasma cells. Cytoplasmic eosinophilic inclusion regions (Negri bodies) in neuronal cells are associated with rabies, but they are not sensitive or specific for the diagnosis of rabies.¹⁷ Viral replication in dorsal root ganglia causes ganglionitis, and it is responsible for the first clinical symptoms of the disease.⁵

Clinical Presentation

The first clinical symptoms of rabies are neuropathic pain, paresthesias, or pruritus at the inoculation site. These symptoms were present in 61% of cases in the United States.^5,18 A prodromal, flulike illness may mark the onset of clinical rabies. Brain involvement causes encephalitis, manifesting as delirium with periods of lucidity. Two major clinical forms of the disease exist: furious and paralytic.

Furious rabies is a manifestation of brainstem encephalitis. Hyperexcitability, autonomic dysfunction, and hydrophobia mark furious rabies. Spasms are induced with olfactory, visual, auditory, and tactile stimuli, causing aerophobia and hydrophobia. These spasms are painful, and the patient remains aware of the pain. Spasms are more prominent in the furious form of the disease. Focal neurologic signs are usually absent in furious rabies. The spasms are differentiated from tetanus by a lack of rigidity or trismus between spastic episodes. Involvement of the autonomic nervous system causes hypersalivation, profuse sweating, tachycardia, and hypertension.

Paralytic rabies results in quadriplegia.¹⁹ It is more common after the bite of a vampire bat in South America. Peripheral neuropathy is responsible for the paralysis in paralytic rabies. Because peripheral nerves are involved, patients lose deep tendon reflexes. The paralysis occurs in an ascending pattern and is associated with pain and fasciculations. The anal sphincter is involved in the quadriplegia.⁶ Death results from paralysis of bulbar and respiratory muscles.

At some point in the course of the disease, spontaneous inspiratory spasms occur in all patients with rabies. These painful inspiratory spasms can escalate to opisthotonos, generalized clonus, and respiratory arrest. Inspiratory spasms persist until death. Without treatment, clinical rabies is uniformly fatal in 2 to 10 days.

Differential Diagnosis

The furious form of rabies is rapidly progressive and is fatal in 1 to 5 days (Table 179.1). The paralytic form of rabies is more slowly progressive, and patients live for up to a month. However, clinical rabies is considered a fatal disease regardless of the clinical manifestation.

Table 179.1 Differential Diagnosis of Rabies

Diagnostic Testing

In the early stage of the disease, tests may show negative results.⁶ The “gold standard” for the diagnosis of rabies is direct fluorescent antibody testing of the brain. Brain biopsy exclusively for the diagnosis of rabies is discouraged.^21,22

Multiple testing techniques exist for the diagnosis of rabies during life. Discuss with the pathologist the preferred sample at your institution. Serum, saliva, and skin samples are commonly used, whereas cerebrospinal fluid, urine, and lacrimal fluid are occasionally tested.^6,23 Do not withhold empiric antirabies therapy to obtain diagnostic studies.

Perform a lumbar puncture for analysis of cerebrospinal fluid for meningitis and encephalitis. Sedate the patient, if necessary, to control spasms. Send cerebrospinal fluid for diagnostic studies according to the patient’s geographic exposure. Perform a toxicologic screen to evaluate for intoxication, but remember that intoxicants may be incidental findings.

Rabies Transmission

Rabies is transmitted only by mammals, both domestic and wild. Common wild animals known to contract and transmit rabies include foxes, skunks, raccoons, coyotes, and bats. Dogs, cats, cattle, and other domestic animals can also contract and transmit rabies.

Patients commonly present after bites and scratches from small rodents, both wild and domestic. In these circumstances, wound care and reassurance are all that is required. Rats, mice, squirrels, chipmunks, hamsters, and guinea pigs do not transmit rabies. Rabbits and other lagomorphs have not been found to have rabies and have never been known to cause rabies.

Postexposure prophylaxis is virtually never indicated after a bite from or exposure to any rodent, so the health department should be consulted before initiating postexposure prophylaxis if the animal’s behavior was suspicious and prophylaxis appears clinically indicated.

To assess the likelihood of rabies exposure, it is helpful to know the distribution of rabid animals in the area. The local or state health department can provide information about rabies prevalence and animal vectors. A list of state health department contact numbers is available through the Centers for Disease Control and Prevention (CDC) at http://www.cdc.gov/ncidod/dvrd/rabies/Links/Links.htm. Moreover, the CDC can be contacted at 877-554-4625 after hours or if the local or state health department is unavailable (http://www.cdc.gov/ncidod/dvrd/rabies/professional/professi.htm).

If the animal involved can carry rabies, determine whether the patient had an exposure (see the “Facts and Formulas” box). Consider any breach in the skin that was caused by teeth to be a bite exposure.^2,23 Exposure to aerosolized virus in a laboratory or cave setting constitutes a nonbite exposure. Saliva, neural tissue, or other infectious material contacting open wounds or mucous membranes constitutes an exposure. Contact of infectious material with intact skin does not constitute an exposure, nor does contact with noninfectious material, such as feces, blood, or urine, or petting a rabid animal. Do not provide postexposure prophylaxis to patients who have not had an exposure.²

Travel Outside the United States

Tens of thousands of people die of rabies worldwide, most commonly after being bitten by an infected dog. In developing countries of Africa, Asia, and Latin America, rabies is common. Preexposure vaccination is indicated only if the patient will have a high likelihood of contact with animals, will remain for an extended period of time, and will have difficulty obtaining postexposure treatment. Even if preexposure prophylaxis is administered, postexposure treatment is still needed.

The World Health Organization (http://www.who.int/rabies/epidemiology) reports that rabies is present on every continent except Antarctica. Of 145 countries reporting, 45 note no cases of rabies. These rabies-free countries include selected islands such as New Zealand, Japan, Fiji, and Barbados, as well as certain developed European countries such as Greece, Portugal, and Scandinavian countries. In Latin America, Chile and Uruguay are noted to be free of rabies.

If a patient has had an exposure outside the United States, contact the CDC regarding the risk and the need for postexposure prophylaxis. Presume that prophylaxis should be initiated unless convincing evidence is present to the contrary. Initiate prophylaxis even if the wound is healed and the exposure was remote.

If a patient has begun postexposure prophylaxis outside the United States, obtain as much information as possible regarding the treatment before the patient’s return to the United States. Contact the CDC or state or local health department regarding how to continue postexposure prophylaxis in this patient.

Human-to-human transmission of rabies is possible. Documented cases have involved inoculation through saliva by biting or kissing.²⁷ Human-to-human transmission has also occurred from the transplantation of infected organs.^28,29 When providing routine health care to a person with rabies, the use of appropriate contact isolation practices prevents rabies exposure in the health care provider.^2,30 No known case of transmission of rabies to a health care worker from a patient exists.⁵ Treat persons who have been stuck with a contaminated needle from a patient with rabies as a rabies exposure. The concern is that the needle may contain neural tissue.

Incubation periods of up to 6 years have been reported for rabies.¹⁷ For this reason, if exposure to rabies may have occurred, start postexposure prophylaxis regardless of the time from the exposure.⁶ Adhere to the postexposure prophylaxis protocol as with any other exposure (see the “Tips and Tricks: Postexposure Prophylaxis” box).

Wound Treatment and Rabies Prevention

Postexposure prophylaxis consists of three steps: wound care, conferring of passive immunity, and active immunization. When World Health Organization guidelines for postexposure prophylaxis are followed, postexposure prophylaxis is effective. Postexposure prophylaxis failures have all involved deviation from the guidelines.²

The first step in rabies postexposure prophylaxis is local wound care. Copiously irrigate the wound with soap and water. Follow with treatment with a virucidal agent, such as povidone-iodine. Wound care alone decreases the chance of contracting rabies.³¹ Failures of postexposure prophylaxis have been attributed to inadequate local wound care.²

The second step in postexposure prophylaxis is passive immunization. It takes approximately 7 days to develop an antibody response to rabies vaccine. Rabies immune globulin (RIG) provides passive immunization until the antibody response begins. Administer 20 units/kg of RIG. This dose is the same for pediatric and adult patients. Infiltrate as much RIG as possible into the wound and tissue immediately surrounding the wound. Administer the remaining dose of RIG intramuscularly at a site remote from the vaccination site.

If the patient presents with a bite or wound that is already infected, clean the wound appropriately. Débride and incise the wound as needed. RIG can be infiltrated safely into an infected wound following proper local wound care.⁶

The third step in postexposure prophylaxis is vaccination (see the “Tips and Tricks: Postexposure Prophylaxis” box). Three cell culture vaccines are available in the United States: human diploid cell vaccine (HDCV), rabies vaccine adsorbed (RVA), and purified chick embryo cell vaccine (PCEC). These vaccines are all equally efficacious, and the dose and administration are the same for all three types.

Administer 1 mL of vaccine intramuscularly. The vaccine is administered intramuscularly into the deltoid muscle of adults. The vaccine can be administered intramuscularly into the deltoid or anterior thigh of a child. Vaccine failures have been recorded for administration of vaccine into sites other than the deltoid of adults.³² Do not administer vaccine into the same intramuscular region as RIG was administered. Do not use the same syringe to administer vaccine and RIG.

The first day of vaccination is day 0. Inform the patient that four additional vaccinations are required, on days 3, 7, 14, and 28. The subsequent doses are the same, 1 mL intramuscularly. Postexposure prophylaxis should not be modified or discontinued unless the animal is found by laboratory testing to be free of rabies. If interruption of the postexposure prophylaxis schedule occurs, contact the local health department or the CDC to determine the new schedule.

Some people have been previously vaccinated against rabies. If they are exposed to rabies, previously vaccinated people undergo a modified vaccination regimen with two doses of vaccine, one dose on day 0 and one dose on day 3 (see the “Tips and Tricks: Postexposure Prophylaxis Vaccination” box). Administer a 1-mL intramuscular dose of vaccine in the deltoid muscle. Instruct the patient to receive another dose of vaccine on day 3. Do not administer RIG to anyone who has been previously immunized. Provide local wound care, as with any exposure.

Because rabies is considered a fatal disease, postexposure prophylaxis is not withheld during pregnancy. Inform pregnant patients that no known fetal anomalies have been linked to rabies postexposure prophylaxis,^33–35 but extensive testing in humans has not been performed. When possible, discuss the case with the patient’s obstetrician.

Patients who are immunocompromised as a result of chronic illness or immune-modulating drugs require monitoring for immune response. Administer the same dose of vaccine and RIG, and provide appropriate wound care. If possible, discuss the case with the patient’s primary physician or infectious disease specialist. Refer the patient to the patient’s primary physician or infectious disease specialist for the remainder of the vaccination course and the appropriate antibody titers. Monitoring for immune response is outside the scope of emergency medicine.

Treatment

Rabies is considered a fatal disease.⁵ Only six known cases of survivors of clinical rabies have been reported, and in five of these cases, patients had some form of rabies immunization before the onset of clinical disease. Four of the six survivors had neurologic devastation.^8–11

Disposition

Patients who have had an exposure to a healthy pet that is undergoing 10 days of observation should be referred to animal control or to the health department. It is the patient’s responsibility to stay in contact with animal control for information regarding the health of the animal.

Patients who have received the first treatment of postexposure prophylaxis are treated as outpatients. When possible, patients should continue the postexposure prophylaxis with a primary care physician or the health department, to ensure continuity of care. If not possible, the patient can return to the ED for the remainder of the postexposure prophylaxis. Patients with suspected clinical rabies require admission to the intensive care unit.