The introduction to this article may not adequately summarize its contents. To comply with Wikipedia's lead section guidelines, it should be expanded to provide an accessible overview of the article's key points.

Rabies virus
EM of rabies virus.
Virus classification
Group: Group V ((-)ssRNA) Order: Mononegavirales Family: Rhabdoviridae Genus: Lyssavirus Species: Rabies virus

Rabies (from Latin: rabies, “madness, rage, fury.” Also known as “hydrophobia”) is a viral zoonotic neuroinvasive disease that causes acute encephalitis (inflammation of the brain) in mammals. It is most commonly caused by a bite from an infected animal, but occasionally by other forms of contact. If left untreated in humans it is almost invariably fatal. In some countries it is a significant killer of livestock.

The rabies virus makes its way to the brain by following the peripheral nerves.^[1] The incubation period of the disease depends on how far the virus must travel to reach the central nervous system, usually taking a few months.^[2]

In the beginning stages of rabies, the symptoms are malaise, headache, and fever, while in later stages it includes acute pain, violent movements, uncontrolled excitements, depressions, and the inability to swallow water (hence the name hydrophobia)^[3]. In the final stages, the patient begins to have periods of mania and lethargy, and coma.^[4] Death generally occurs due to respiratory insufficiency.^[5]

In non-vaccinated humans, rabies is almost invariably fatal after neurological symptoms have developed, but prompt post-exposure vaccination may prevent the virus from progressing. There are only six known cases of a person surviving symptomatic rabies, and only two known cases of survival in which the patient received no rabies-specific treatment either before or after illness onset.^[6]

[edit] Virology

Please help improve this article or section by expanding it. Further information might be found on the talk page. (October 2008)

[edit] Classification

The rabies virus is a member of the Lyssavirus genus. This genus of RNA viruses also includes the Aravan virus, Australian bat lyssavirus, Duvenhage virus, European bat lyssavirus 1, European bat lyssavirus 2, Irkut virus, Khujand virus, Lagos bat virus, Mokola virus and the West Caucasian bat virus.

[edit] Structure

Lyssaviruses have helical symmetry, so their infectious particles are approximately cylindrical in shape. This is typical of plant-infecting viruses; human-infecting viruses more commonly have cubic symmetry and take shapes approximating regular polyhedra. Negri bodies in the infected neurons are pathognomonic.

The virus has a bulletlike shape with a length of about 180 nm and a cross-sectional diameter of about 75 nm. One end is rounded or conical and the other end is planar or concave. The lipoprotein envelope carries knob-like spikes composed of Glycoprotein G. Spikes do not cover the planar end of the virion (virus particle). Beneath the envelope is the membrane or matrix (M) protein layer which may be invaginated at the planar end. The core of the virion consists of helically arranged ribonucleoprotein.

[edit] Genome

The genome is unsegmented linear antisense RNA. Also present in the nucleocapsid are RNA dependent RNA transcriptase and some structural proteins.

[edit] Life cycle

From the source of wound of entry, the rabies virus travels quickly along the neural pathways to the central nervous system. There the virus further spreads to other organs. The saliva glands located in the tissues of the mouth and cheeks receive high concentrations of the virus, thus allowing for it to be further transmitted. Fatality can occur within anywhere from two days to five years from the time of initial infection.^[7][8]

[edit] Prevention

Rabies can be prevented by vaccination, both in humans and other animals. Virtually every infection with rabies resulted in death, until Louis Pasteur and Emile Roux developed the first rabies vaccination in 1885. This vaccine was first used on a human on July 6, 1885 – nine-year old boy Joseph Meister (1876–1940) had been mauled by a rabid dog.^[9]

Their vaccine consisted of a sample of the virus harvested from infected (and necessarily dead) rabbits, which was weakened by allowing it to dry for 5 to 10 days. Similar nerve tissue-derived vaccines are still used now in some countries, and while they are much cheaper than modern cell culture vaccines, they are not as effective and carry a certain risk of neurological complications.

The human diploid cell rabies vaccine (H.D.C.V.) was started in 1967. Human diploid cell rabies vaccines are made using the attenuated Pitman-Moore L503 strain of the virus. Human diploid cell rabies vaccines have been given to more than 1.5 million humans as of 2006. Newer and less expensive purified chicken embryo cell vaccine, and purified Vero cell rabies vaccine are now available. The purified Vero cell rabies vaccine uses the attenuated Wistar strain of the rabies virus, and uses the Vero cell line as its host.

Some recent works have shown that during lethal rabies infection the blood-brain barrier (BBB) does not allow anti-viral immune cells to enter the brain, the primary site of rabies virus replication.^[10] This aspect contributes to the pathogenicity of the virus and artificially increasing BBB permeability promotes viral clearance.^[11] Opening the BBB during rabies infection has been suggested as a possible novel approach to treat the disease.^{[citation needed]}

[edit] Pre-exposure prophylaxis

Currently pre-exposure immunization has been used on domesticated and normal non-human populations. In many jurisdictions, domestic dogs, cats, and ferrets are required to be vaccinated. A pre-exposure vaccination is also available for humans, most commonly given to veterinarians and those traveling to regions where the disease is common, such as India. Most tourists do not need such a vaccination, just those doing substantial non-urban activities. However, should a vaccinated human be bitten by a carrier, failure to receive subsequent post-exposure treatment could be fatal, although post-exposure treatment for a vaccinated human is far less extensive than that which would normally be required by one with no pre-exposure vaccination.

In 1984 researchers at the Wistar Institute developed a recombinant vaccine called V-RG by inserting the glycoprotein gene from rabies into a vaccinia virus.^[12] The V-RG vaccine has since been commercialised by Merial under the trademark Raboral. It is harmless to humans and has been shown to be safe for various species of animals that might accidentally encounter it in the wild, including birds (gulls, hawks, and owls).^[13]

V-RG has been successfully used in the field in Belgium, France, Germany and the United States to prevent outbreaks of rabies in wildlife. The vaccine is stable under relatively high temperatures and can be delivered orally, making mass vaccination of wildlife possible by putting it in baits. The plan for immunization of normal populations involves dropping bait containing food wrapped around a small dose of the live virus. The bait would be dropped by helicopter concentrating on areas that have not been infected yet. Just such a strategy of oral immunization of foxes in Europe has already achieved substantial reductions in the incidence of human rabies. In November 2008, Germany had been free of new cases for two years and is therefore currently believed as being rabies-free, together with few other countries (see below). A strategy of vaccinating “neighborhood dogs” in Jaipur, India, (combined with a sterilization program) has also resulted in a large reduction in the number of human cases.^[14]

[edit] Post-exposure prophylaxis

Treatment after exposure, known as post-exposure prophylaxis or “P.E.P.”, is highly successful in preventing the disease if administered promptly, generally within six days of infection. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is very effective at reducing the number of viral particles. “If available, a virucidal antiseptic such as povidone-iodine, iodine tincture, aqueous iodine solution or alcohol (ethanol) should be applied after washing.”^[15] Exposed mucous membranes such as eyes, nose or mouth should be flushed well with water. In the United States, patients receive one dose of immunoglobulin and five doses of rabies vaccine over a twenty-eight day period. One-half the dose of immunoglobulin is injected in the region of the bite, if possible, with the remainder injected intramuscularly away from the bite. This is much less painful compared with administering immunoglobulin through the abdominal wall with a large needle, as was done in the past. The first dose of rabies vaccine is given as soon as possible after exposure, with additional doses on days three, seven, fourteen, and twenty-eight after the first. Patients that have previously received pre-exposure vaccination do not receive the immunoglobulin, only the post-exposure vaccinations on day 0 and 3. Since the widespread vaccination of domestic dogs and cats and the development of effective human vaccines and immunoglobulin treatments, the number of recorded deaths in the U.S. from rabies has dropped from one hundred or more annually in the early twentieth century, to 1–2 per year, mostly caused by bat bites, which may go unnoticed by the victim and hence untreated.

Most official documentation on rabies on the internet and otherwise warn that treatment becomes futile with the onset of prodrome (when symptoms begin to appear). These texts are written to convince the layman not to delay seeking treatment (and rightly so).^{[citation needed]} However, this may also lead them to falsely conclude that their situation is not an urgency and that treatment is possible up until the very end of the incubation period, as it may last 1 to 3 months on average; or it may at least convince them that it is safe to delay treatment by a few days. While the virus is treatable only during the incubation period, it is important to note that it is not treatable during its entirety. The disease becomes untreatable long before the onset of the prodromal stage, or the first signs of symptoms. Rabies is treatable while the virus is present in tissues composed of cells other than neurons, such as skin and muscle. However, once the infection spreads to a neuron, the virus is sequestered from the immune system and will eventually make its way to the spinal cord and then to the brain. Treatment at this point is futile, even though symptoms may begin to appear weeks or even months later. Therefore, it is essential that P.E.P. be administered as soon as possible. Begun without delay, or very little delay, P.E.P. is highly effective against rabies.^{[citation needed]} In the case where there has been a significant delay in administering P.E.P., the treatment should be administered regardless of that delay.

[edit] Symptoms

A patient with rabies, 1959.

The period between infection and the first flu-like symptoms is normally two to twelve weeks, but can be as long as two years. Soon after, the symptoms expand to slight or partial paralysis, cerebral dysfunction, anxiety, insomnia, confusion, agitation, abnormal behavior, paranoia, terror, hallucinations, progressing to delirium.^{[citation needed]} The production of large quantities of saliva and tears coupled with an inability to speak or swallow are typical during the later stages of the disease; this can result in “hydrophobia”, where the victim has difficulty swallowing because the throat and jaw become slowly paralyzed, shows panic when presented with liquids to drink, and cannot quench his or her thirst. The disease itself was also once commonly known as hydrophobia, from this characteristic symptom. The patient experiences the response of “foaming at the mouth” as a result of the body's inability to quench its thirst; essentially, overproduction of saliva a last-resort attempt at retaining fluids.

Death almost invariably results two to ten days after the first symptoms; the few humans who are known to have survived the disease^{[citation needed]} were all left with severe brain damage, with the exception of Jeanna Giese (see below). It is neurotropic in nature.

[edit] Diagnosis

The reference method for diagnosing rabies is by performing PCR or viral culture on brain samples taken after death. The diagnosis can also be reliably made from skin samples taken before death.^[16] It is also possible to make the diagnosis from saliva, urine and cerbrospinal fluid samples, but this is not as sensitive.Inclusion bodies called Negri bodies are 100% diagnostic for rabies infection,but found only in 20% cases.

The differential diagnosis in a case of suspected human rabies may initially include any cause of encephalitis, particularly infection with viruses such as herpesviruses, enteroviruses, and arboviruses (e.g., West Nile virus). The most important viruses to rule out are herpes simplex virus type 1, varicella-zoster virus, and (less commonly) enteroviruses, including coxsackieviruses, echoviruses, polioviruses, and human enteroviruses 68 to 71. In addition, consideration should be given to the local epidemiology of encephalitis caused by arboviruses belonging to several taxonomic groups, including eastern and western equine encephalitis viruses, St. Louis encephalitis virus, Powassan virus, the California encephalitis virus serogroup, and La Crosse virus.

New causes of viral encephalitis are also possible, as was evidenced by the recent outbreak in Malaysia of some 300 cases of encephalitis (mortality rate, 40%) caused by Nipah virus, a newly recognized paramyxovirus.^[17] Similarly, well-known viruses may be introduced into new locations, as is illustrated by the recent outbreak of encephalitis due to West Nile virus in the eastern United States.^[18] Epidemiologic factors (e.g., season, geographic location, and the patient’s age, travel history, and possible exposure to animal bites, rodents, and ticks) may help direct the diagnostic workup.

Cheaper rabies diagnosis will be possible for low-income settings according to research reported on the Science and Development Network website in 2008. Accurate rabies diagnosis can be done ten times more cheaply, according to researchers from the Farcha Veterinary and Livestock Research Laboratory and the Support International Health Centre in N'Djamena, Chad. The scientists evaluated a method using light microscopy, cheaper than the standard tests, and say this could provide better rabies control across Africa.^[19]

[edit] Treatments

[edit] Induced coma

Main article: Jeanna Giese

In 2005, the case of Jeanna Giese, a girl of 15 who survived acute, invaccinated rabies was reported, indicating the successful treatment of rabies through induction of a coma.^[20] This treatment approach was based on the theory that rabies' detrimental effects were caused by temporary dysfunctions of the brain, and that the induction of a coma, by producing a temporary partial stop in brain function, would protect the brain from damage while the body built up an immune response to the virus. After thirty-one days of isolation and seventy-six days of hospitalization, she was released from the hospital, having survived rabies.

Rodney Willoughby Jr., the primary care physician in this case published in the April 2007 issue of Scientific American.^[21] He notes that subsequent failures of what he calls the Milwaukee protocol did not use the cocktail of drugs used during the treatment of Giese. A point he makes for future research is the relationship of the virus to depletion of biopterin in the brain.

Later attempts to use the same treatment have failed, but in April, 2008, in Cali, Colombia, it was reported (by local newspapers) that an 11-year-old may have recovered successfully after induction of coma ^[22]. This patient was infected on February 15 when several children were bitten by a cat in Santander de Quilichao, a small town near Cali. However, this claim has not been verified.

In November, 2008, a 15-year-old Brazilian boy was reported to have recovered from symptomatic rabies^[23], also using the Milwaukee protocol.

[edit] Epidemiology

[edit] Vectors

TEM micrograph with numerous rabies virions (small dark-grey rod-like particles) and Negri bodies (the larger pathognomonic cellular inclusions of rabies infection).

Any mammal may become infected with the rabies virus and develop symptoms, including humans. Most animals can be infected by the virus and can transmit the disease to humans. Infected bats, monkeys, raccoons, foxes, skunks, cattle, wolves, dogs or cats provide the greatest risk to humans. Rabies may also spread through exposure to infected domestic farm animals, groundhogs, weasels and other wild carnivores. Rodents (mice, squirrels etc) are seldom infected.^{[citation needed]}

The virus is usually present in the nerves and saliva of a symptomatic rabid animal.^[24][25] The route of infection is usually, but not necessarily, by a bite. In many cases the infected animal is exceptionally aggressive, may attack without provocation, and exhibits otherwise uncharacteristic behaviour.^[26] Transmission may also occur via an aerosol through mucous membranes; transmission in this form may have happened in people exploring caves populated by rabid bats.

Transmission between humans is extremely rare, although it can happen through transplant surgery (see below for recent cases), or, even more rarely, through bites, kisses or sexual relations.

After a typical human infection by bite, the virus enters the peripheral nervous system. It then travels along the nerves towards the central nervous system. During this phase, the virus cannot be easily detected within the host, and vaccination may still confer cell-mediated immunity to prevent symptomatic rabies. Once the virus reaches the brain, it rapidly causes encephalitis. This is called the “prodromal” phase. At this time, treatment is useless. Then symptoms appear. Rabies may also inflame the spinal cord producing myelitis.

[edit] Prevalence

Main article: Prevalence of rabies

Rabies-free jurisdictions, as of January 2006: Australia, New Zealand, Singapore, Fiji, Germany, Guam, Hawaii, the United Kingdom, Republic of Ireland, Norway, Sweden, Finland, Iceland, Japan and Taiwan/ROC.

The rabies virus survives in wide-spread, varied, rural fauna reservoirs. However, in Asia, parts of America and large parts of Africa, dogs remain the principal host. Mandatory vaccination of animals is less effective in rural areas. Especially in developing countries, pets may not be privately kept and their destruction may be unacceptable. Oral vaccines can be safely distributed in baits, and this has successfully reduced rabies in rural areas of France, Ontario, Texas, Florida and elsewhere, like in the City of Montréal (Québec) where baits are successfully used among raccoons in the Mont-Royal park area. Vaccination campaigns may be expensive, and a cost-benefit analysis can lead those responsible to opt for policies of containment rather than elimination of the disease.

Almost all human deaths caused by rabies originate from Asia and Africa. There are an estimated 55,000 human deaths annually from rabies worldwide, with about 31,000 in Asia, and 24,000 in Africa.^[27] One of the sources of recent flourishing of rabies in East Asia is the pet boom. China introduced in the city of Beijing the “one-dog policy” in November 2006 to control the problem.^[28] India has been reported as having the highest rate of human rabies in the world, primarily because of stray dogs.^[29]

Rabies was once rare in the United States outside the Southern states, but raccoons in the mid-Atlantic and northeast United States have been suffering from a rabies epidemic since the 1970s, which is now moving westwards into Ohio.^[30] In the midwestern United States, skunks are the primary carriers of rabies, composing 134 of the 237 documented non-human cases in 1996. The most widely distributed reservoir of rabies in the United States, however, and the source of most human cases in the U.S., are bats.^{[citation needed]}

[edit] Rabies and animals

Please help improve this section by expanding itwith: information from the main article. Further information might be found on the talk page. (October 2008)

Main article: Rabies and animals

Aerially distributed wildlife rabies vaccine in a bait from Estonia.

Rabies is infectious to mammals. Three stages of rabies are recognized in dogs and other animals. The first stage is a one to three day period characterized by behavioral changes and is known as the prodromal stage. The second stage is the excitative stage, which lasts three to four days. It is this stage that is often known as furious rabies due to the tendency of the affected dog to be hyperreactive to external stimuli and bite at anything near. The third stage is the paralytic stage and is caused by damage to motor neurons. Incoordination is seen due to rear limb paralysis and drooling and difficulty swallowing is caused by paralysis of facial and throat muscles. Death is usually caused by respiratory arrest.^[31]

[edit] Recent cases

This section may contain inappropriate or misinterpreted citations that do not verify the text. Please help improve this article by checking for inaccuracies. (November 2008) (help, talk, get involved!)

Several recently publicized cases have stemmed from bats, which are known to be a vector for rabies.

In October 2004 a brown bear killed one human and injured several others near the city of Braşov in Central Romania. The bear was killed by human hunters and diagnosed with rabies. More than one hundred humans were vaccinated afterwards.

Rabies is known to have been transmitted between humans by transplant surgery on rare occasions.

Infections by corneal transplant have been reported in Thailand (two cases), India (two cases), Iran (two cases),^[32] the United States (one case), and France (also a single case).^[33] Details of two further cases of infection resulting from corneal transplants were described in 1996.h

In June 2004, three organ recipients died in the United States from rabies transmitted in the transplanted kidneys and liver of an infected donor from Texarkana.^[34] There were bats near the donor's home, and the donor had told others that he had been bitten.^[35] The donor is now reported to have died of a cerebral hemorrhage, the culmination of an unidentified neurological disorder, although recipients are said to have been told the cause of death had been a car crash. Marijuana and cocaine were found in the donor's urine at the time of his death, according to a report in The New England Journal of Medicine.^[36]

"[The surgeons] thought he had suffered a fatal crack-cocaine overdose, which can produce symptoms similar to those of rabies. ‘We had an explanation for his condition,’ says Dr. Goran Klintmalm, a surgeon who oversees transplantation at Baylor University Medical Center, where the transplants occurred. ‘He’d recently smoked crack cocaine. He’d hemorrhaged around the brain. He’d died. That was all we needed to know.’ Because of doctor-patient confidentiality rules, doctors involved with this case would not talk about it on the record, but a few did say that if no cocaine was found in the donor’s blood, the E.R. doctors might have investigated his symptoms more aggressively instead of assuming he had overdosed. (Because no autopsy was done, doctors have not been able to establish whether the rabies or the drugs actually killed him.)"^[37]

In February 2005, three German patients in Mainz and Heidelberg were diagnosed with rabies after receiving various organs and cornea transplants from a female donor. Two of the infected people died. Three other patients who received organs from the woman have not yet shown rabies symptoms. The 26 year old donor had died of heart failure in December 2004 after consuming cocaine and ecstasy. In October 2004, she had visited India, one of the countries worst affected by rabies worldwide. Dozens of medical staff were vaccinated against rabies in the two hospitals as a precautionary measure. Associated Press reports that "Donated organs are never tested for rabies. The strain detected in the victims’ bodies is one commonly found in bats, health officials said." According to CNN, "Rabies tests are not routine donor screening tests, Virginia McBride, public health organ donation specialist with the Health Resources and Services Administration, said. The number of tests is limited because doctors have only about six hours from the time a patient is declared brain-dead until the transplantation must begin for the organs to maintain viability."

Recently new symptoms of rabies of wild animals have been observed, namely in foxes. Probably at the beginning of the prodromal stage foxes, who are extremely cautious by nature, absolutely lose wild instincts. Animals come into settlements, reach for people, and behave as if tame. How long such "euphoria" lasts is not known. But even in such status the animal is extremely dangerous, as its saliva and excretions still contain the virus. In an August 2008 blog article^{[unreliable source?]}, one author observed and photographed such a subject.

[edit] History

Please help improve this section by expanding itwith: currently the following web page [3]. Further information might be found on the talk page. (October 2008)

[edit] Cultural impact

Because of its potentially violent nature, rabies has been known for a long time. Since 3000 B.C., the term "rabies" is possibly derived from the Sanskrit word "rabhas" or "to do violence". The Greeks derived the word "lyssa", which is derived from "lud" or "violent", this terminology is used in the name of the genus of rabies lyssavirus.^[38] The first written record of rabies is in the Codex of Eshnunna (ca. 1930 BC), which dictates that the owner of a dog showing symptoms of rabies should take preventative measure against bites. If a person was bitten by a rabid dog and later died, the owner was fined heavily.^[39]

In the 19th century rabies has been considered a scourge for its prevalence. Fear of rabies related to methods of transmissions was almost irrational. This, however, gave Louis Pasteur ample ability to test post-exposure treatments in 1895. It was not until 1960 when the virus itself was isolated.^[40]

[edit] Popular culture

• Cujo, a Stephen King novel and film about a mother and son being terrorized by a rabid dog.
• Histories, an episode of the television medical drama House (TV Series) where a homeless woman suffers from rabies.
• Old Yeller, a novel and film that involves a frontier dog becoming infected by a rabid wolf.
• I Drink Your Blood, a 1970's cult horror film about a gang of Satanic hippies who get infected with rabies.
• Quarantine, a 2008 horror film involving a new strain of rabies which causes its subjects to succumb to uncontrollable violence, rage, and cannibalism.
• Rant, a Chuck Palahniuk novel about killing with the rabies virus.
• My Lunch, an episode of the comedy-drama Scrubs which refers to a case involving rabies transmitted by organ transplants.
• Their Eyes Were Watching God, Tea Cake, a character in the novel, is mentally affected by a bite from a rabid dog.
• Fun Run, an episode of the US television sitcom The Office in which Michael hits Meredith with his car but while in the hospital finds out she may possibly have been exposed to rabies via several animal bites (bat, rat and racoon).
• Left 4 Dead, a videogame released in 2008 that pits hordes of humans infected with an advanced form of the rabies virus against 4 immune survivors as they fight their way through various scenarios to rescue.
• 28 Days Later, a 2002 zombie horror film, first one to introduce a mutated rabies virus as the cause for a zombie plague, the zombies being infected but otherwise living human beings rather than reanimated corpses. A sequel, namely 28 Weeks Later, came out in 2008.

[edit] See also

Wikimedia Commons has media related to: Rabies

Wikinews has related news:

Rabies

Look up Rabies in
Wiktionary, the free dictionary.

• Alliance for Rabies Control
• Neurotropic virus
• World Rabies Day

[edit] References

[edit] Notes

[edit] Bibliography

[edit] Further reading

[edit] External links