Disease
Rabies

Author
Pamela Russillo, BIOL 230, Spring 2009

Causative Agents
A member of the Rhabdoviridae family, rabies virus is enveloped and bullet-shaped, approximately 70 nm (def) wide and 180 nm long, with a negative, single-stranded RNA genome. Rabies is not a hardy virus in the environment and is very susceptible to dehydration, sunlight, heat, and many soap solutions and disinfecting agents.

Epidemiology
Rabies is a worldwide zoonotic (def) disease that infects the central nervous system (def) of mammals, causing encephalitis (def). Once symptoms appear, rabies is almost universally fatal in animals and humans. Worldwide, between 35,000 and 55,000 people die from rabies annually, although underreporting is suspected in many parts of the world. In the United States, human fatalities from rabies are rare; only 1 to 4 cases are reported each year.

Prior to the onset of clinical symptoms, post-exposure prophylaxis (def) can be administered to prevent progression of the infection to full-blown rabies. Each year, 10 million people worldwide, including 20,000 to 40,000 in the United States, receive post-exposure vaccinations after suspected exposure to the virus.
Rabies virus is present throughout most of the world, although several island territories, including Hawaii, the United Kingdom, Australia, New Zealand, and Japan, are considered rabies-free. Human rabies is almost always contracted through the bite of a rabid animal. Therefore, occurrence of human infections reflects levels of infected animal populations and the amount of contact between those populations and people. The prevalence of rabies in humans is much higher in developing nations, particularly those in Africa, Asia, South America, and India, than in developed nations. Poor countries have few resources for vaccination programs aimed at controlling rabies in domestic and wild animal populations. Additionally, effective post-exposure treatment is often not widely available or accessible in such areas.
Age, gender, and race are not predisposing factors for rabies infection. However, people who are more likely to have contact with high-risk animal populations face an increased risk of infection.

Transmission
Any mammal can become infected with the rabies virus, but only some species are important reservoirs (def) posing a threat to humans. High-risk species vary by geographic location. Worldwide, unvaccinated domestic dogs transmit the most rabies infections in people, especially in parts of Mexico, South America, Africa, and Asia. Wild canines such as coyotes, jackals, wolves, and foxes are also common sources of animal-to-human transmission throughout the world.

By contrast, in the United States, rabid domestic dogs are relatively rare due to widespread adoption of vaccination programs that began in the 1940s. Rabies is seen in less than 10% of domestic animals, most often reported in cats, followed by cattle and dogs. Wildlife accounts for over 90% of animal rabies in the United States. Insectivorous (def) bats, raccoons, foxes, skunks and coyotes are the primary reservoirs posing the greatest risks to people in the U.S.

The saliva and central nervous system tissue of rabid hosts are considered infectious. Rabies virus is typically transmitted in the saliva via a bite wound, either animal-to-animal or animal-to-human. It is also possible, though uncommon, for virus transmission to occur when infected saliva or airborne secretions are introduced to a scratch or fresh cut on the skin, or to mucous membranes of the lips, nose, or eyes.
Extremely rare person-to-person transmission of rabies has been documented via organ transplantation. Eight such cases have occurred in cornea transplant recipients. In 2004, the United States and Germany reported the first cases of rabies transmission via solid organ transplants (lung, liver, and kidneys). Seven patients died from rabies after receiving organs from one of two donors who had unknown rabies infections. No other person-to-person infections have ever been documented, although it is theoretically possible. As a precaution, healthcare workers, family members, and others who may have had close contact with a patient’s saliva or other bodily fluids may opt to receive post-exposure prophylaxis.

Signs and Symptoms
Rabies virus infects the central nervous system (CNS) of mammalian hosts, resulting in acute (def) encephalitis and death unless treatment is initiated prior to the onset of clinical symptoms. Progression of the disease is recognized in the following stages:

The incubation period (def), during which the host remains asymptomatic, is exceptionally variable and can range from less than 10 days to several years, with 1 to 3 months being most typical. Rarely, incubation periods between 5 and 19 years have been documented, suggesting the possibility that rabies virus may be capable of latency (def). Rabies antigen (def) and virus are generally undetectable during this period and no antibody (def)) response is observed.

The prodromal (def) period begins when the virus enters the CNS. The first signs of illness appear and the disease progresses rapidly and irreversibly. Nonspecific symptoms are frequently mistaken for those of the common cold or flu, such as headache, fatigue, appetite loss, fever, chills, nausea, vomiting, diarrhea, pharyngitis (def), cough, and general malaise. Other generalized complaints such as insomnia, depression, anxiety, or irritability may be present. About 50% of individuals experience pain or parathesia (def) at the site of initial infection, a symptom distinctly indicative of rabies. It is possible for this to be the only clinical manifestation during the 2 to 10 day prodromal phase.

The acute neurologic period lasts 7 days or less and is marked by the onset of obvious CNS dysfunction. Either furious or paralytic rabies develops. Furious rabies is the most common manifestation and is so named because patients experience episodes of severe agitation and hyperactivity. Such episodes may include thrashing, muscle twitching, hallucinations, and seizures. Two hallmark characteristics of furious rabies exhibited in 50% of patients are hydrophobia (def) and aerophobia (def), brought on by painful throat spasms, dysphagia (def), and sensations of choking.  Accompanying symptoms often include excessive salivation, hyperventilation, hypertension (def) and tachycardia (def). Furious rabies can result in sudden death from respiratory or cardiac failure or, more commonly, progresses to paralysis and coma.

Paralytic rabies is the rarer form of the disease, developing in 20% of patients. Progressive paralysis is the dominant symptom, along with fever, and headache. The agitation and hyperactivity evident in furious rabies are absent. Additional symptoms may include disorientation, dysphagia, and hypersalivation. Patients deteriorate rapidly into delirium and coma.

Duration of coma varies, but death generally results within days or weeks following respiratory or cardiac arrest.

Prevention and Treatment
Reduction of rabies in animal populations is paramount to prevent human infections. In this effort, many countries employ vaccination programs for domestic, and sometimes wild, animal reservoirs. In addition, people may reduce their risk of infection by avoiding contact with high-risk animals as much as possible.
Prior to the onset of clinical symptoms, people with known or suspected rabies exposure can receive post-exposure prophylaxis (PEP) to prevent progression of an infection to full-blown rabies. Treatment types, availability, and effectiveness vary throughout the world. However, post-exposure treatment available in the United States, as described below, is nearly 100% successful.

Because the incubation period of rabies is uncertain and highly variable, PEP should be initiated as soon as possible after exposure. Optimal effectiveness of PEP depends upon proper and timely administration of three components: immediate and thorough wound cleansing; one dose of human rabies immune globulin (HRIG) (def); and a 5-dose series of rabies vaccine. HRIG provides immediate, short-term protection (1 to 2 weeks), allowing sufficient time for the vaccine to stimulate antibody response. HRIG should be administered on the first day of PEP (day 0), but can be given up until day 7 of treatment.  The full dose of HRIG, or as much as possible, is injected at the wound site; any remainder is injected intramuscularly at an alternate site, often the buttocks. Rabies vaccine is an inactivated virus vaccine (def) injected intramuscularly, usually in the upper arm of adults or the outer thigh of young children. The initial doses of vaccine is given on the first day of PEP (day 0), with four subsequent doses given on days 3, 7, 14, and 28. Anyone who has previously received rabies vaccine does not require HRIG. Two vaccine booster shots, sufficient to stimulate antibody response, are given on days 0 and 3.

Individuals whose occupation or recreational activities place them at increased risk of rabies exposure should consider pre-exposure vaccination consisting of three doses of vaccine given on days 0, 7, and 21 or 28. If subsequently exposed to the virus, only two doses of booster vaccine are necessary.

Once symptomatic, there is no effective treatment for rabies. Although intensive life support therapies may prolong survival for weeks or months, a fatal outcome is virtually certain. There is only one documented case, reported in Wisconsin in 2004, of recovery from symptomatic rabies in a person who had not received any pre- or post-exposure prophylaxis. The patient recovered after an experimental treatment involving induced coma and a combination of medications. However, subsequent trials of the same treatment in other patients have been unsuccessful.

Bibliography
Centers for Disease Control and Prevention [CDC], National Center for Zoonotic, Vector-Borne, & Enteric Diseases. (n.d.) Rabies. Retrieved April 11, 2009 from http://www.cdc.gov/rabies/

eMedicineHealth. (n.d.) Rabies. Retrieved April 11, 2009 from http://www.emedicinehealth.com/rabies/article_em.htm

Gompf, Sandra G. (October 3, 2008). Rabies. Retrieved April 11, 2009 from http://emedicine.medscape.com/article/220967-overview

Rupprecht, Charles E. (1996). Rhabdoviruses: Rabies virus. InSamuel Baron (Ed.), Medical Microbiology (4th ed.).Retrieved April 11, 2009 from http://gsbs.utmb.edu/microbook/ch061.htm

World Health Organization. (n.d.) Rabies. Retrieved April 11, 2009 from http://www.who.int/rabies/epidemiology/en/