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Rabies
Specialty	Infectious diseases, veterinary medicine

Rabies (Latin, rabies, "madness, rage, fury") is a viral zoonotic disease that causes acute encephalitis in mammals. 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.

Transmission and symptoms

Cats, dogs, ferrets, raccoons, skunks, foxes, wolves, coyotes, bears, bats, and horses can become rabid. Squirrels, chipmunks, other rodents (except beavers), and rabbits are very seldom infected. Rabies may also be present in a so-called "paralytic" form, rendering the victim abnormally quiet and withdrawn.

The virus is usually present in the saliva of a symptomatic rabid animal; the route of infection is nearly always by a bite, and in many cases in animals, causes the victim to be exceptionally aggressive, attack without provocation, and exhibit otherwise uncharacteristic behavior. Transmission has occurred 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, though it can happen through transplant surgery (see below for recent cases), or even more rarely through bites or kisses.

After a typical human infection by bite, the virus directly or indirectly 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 preempt symptomatic rabies. Once the virus reaches the brain, it rapidly causes encephalitis and symptoms appear. It may also inflame the spinal cord producing myelitis.

The period between infection and the first flu-like symptoms is normally three to twelve weeks, but can be as long as two years. Soon after, the symptoms expand to cerebral dysfunction, anxiety, insomnia, confusion, agitation, abnormal behavior, hallucinations, progressing to delirium. 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". Death almost invariably results two to ten days after the first symptoms; the few humans who are known to have survived the disease were all left with severe brain damage, with the recent exception of Jeanna Giese (see below).

The virus

The rabies virus is a Lyssavirus. 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 West Caucasian bat virus. 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.

Biopsy shows typical Negri bodies in the infected neurons.

The virus has a bullet-like 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. 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. The genome is unsegmented linear antisense R.N.A. Also present in the nucleocapsid are RNA dependent R.N.A. transcriptase and some structural proteins.

Prevention

There is no known cure for symptomatic rabies, but it can be prevented by vaccination, both in humans and other animals. Virtually every infection with rabies was a death sentence, until Louis Pasteur and Emile Roux developed the first rabies vaccination in 1885. This vaccine was first used on nine-year old boy Joseph Meister (1876-1940), on July 6, 1885, after the boy was mauled by a rabid dog.

Their vaccine consisted of a sample of the virus harvested from infected (and necessarily dead) rabbits, which was weakened by allowing it to dry. 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 chick 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.

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, within fourteen days after infection. The first step is immediately washing the wound with soap and water, which is very effective at reducing the number of viral particles. 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 to when immunoglobulin was administered through the abdominal wall with a large needle. 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 preexposure vaccination do not receive the immunogolbulin, only the post-exposure vaccinations. Since the wide-spread 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.

P.E.P. is effective in treating rabies because the virus must travel from the site of infection through the peripheral nervous system (nerves in the body) before infecting the central nervous system (brain and spinal cord) and glands to cause lethal damage. This travel along the nerves is usually slow enough that vaccine and immunoglobulin can be administered to protect the brain and glands from infection. The amount of time this travel requires is dependent on how far the infected area is from the brain: if the victim is bitten in the face, for example, the time between initial infection and infection of the brain is very short and P.E.P. may not be successful.

Preexposure prophylaxis

Currently preexposure 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 new, orally active, genetically recombined virus vaccine for raccoon rabies awaits licensing by the U.S. Department of Agriculture as of 2006. A gene that produces a protein in the rabies virus outer coat was inserted into a live vaccinia virus using recombinant D.N.A. technology. When the modified vaccinia virus infects a normal animal, it produces the antigenic protein normally made by the rabies virus. The victim's systems recognize the protein as foreign, and the animal develops active immunity. 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.

A preexposure 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 would not need such a vaccination, just those doing substantial non-urban activities.) However, should a vaccinated human be bitten by a possible victim, they must have subsequent post-exposure treatment. Failure to do so could be fatal. Such post-exposure treatment is far less extensive than what would normally be required by one with no preexposure vaccination.

Induced coma treatment

In 2005, the case of a girl of 15 who survived acute, unvaccinated rabies was reported, indicating the successful treatment of rabies through induction of a coma. 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. Later attempts to use the same treatment have failed.

Prevalence

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More than 99% of all human deaths from rabies occur in Africa, Asia and South America; India alone reports thirty thousand deaths annually. China recorded 2,254 rabies cases in the first nine months of 2006, up 30% on the same period in 2005 and had overtaken tuberculosis and AIDS as the country's most deadly disease. One of the sources of recent flourishing of rabies in the East Asia is the pet boom. China introduced the "One-dog policy" in November 2006 to control the issue.

Dog licensing, killing of stray dogs, muzzling and other measures contributed to the eradication of rabies from the United Kingdom in the early 20th century. More recently, large-scale vaccination of cats, dogs and ferrets has been successful in combating rabies in some developed countries.

Rabies virus survives in wide-spread, varied, rural fauna reservoirs. However, in Asia, parts of Latin America and large parts of Africa, dogs remain the principal host. Mandatory vaccination of non-human 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 impacted rabies in rural areas of France, Ontario, Texas, Florida and elsewhere. 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.

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.

The particular variant of the virus has been identified in the southeastern United States raccoon population since the 1950s, and is believed to have traveled to the northeast as the result of infected raccoons being among those caught and transported from the southeast to the northeast by human hunters attempting to replenish the declining northeast raccoon population. As a result, urban residents of these areas have become more wary of the large but normally unseen urban raccoon population. It has become the common assumption that any raccoon seen diurnally is infected; certainly the reported behavior of most such animals appears to show some sort of illness, and autopsies usually confirm rabies. Whether as a result of increased vigilance or only the common human avoidance reaction to any other animal not normally seen, such as a raccoon, there has only been one documented human rabies case as a result of this variant. Cite error: The <ref> tag has too many names (see the help page). This does not include, however, the greatly increasing rate of prophylactic rabies treatments in cases of possible exposure, which numbered fewer than one hundred humans annually in New York State before 1990, for instance, but rose to approximately ten thousand annually between 1990 and 1995. At approximately $1500 per course of treatment, this represents a considerable public health expenditure. Raccoons do constitute approximately 50% of the approximately eight thousand documented non-human rabies cases in the United States. Domestic animals constitute only 8% of rabies cases, but are increasing at a rapid rate.

In the midwestern United States, skunks are the primary carriers of rabies, comprising one hundred and thirty-four of the two hundred and thirty-seven 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. Nineteen of the twenty-two human rabies cases documented in the United States between 1980 and 1997 have been identified genetically as bat rabies. In many cases, victims are not even aware of having been bitten by a bat, assuming that a small puncture wound found after the fact was the bite of an insect or spider; in some cases, no wound at all can be found, leading to the hypothesis that in some cases the virus can be contracted via inhaling airborne aerosols from the vicinity of a bat or bats. For instance, the Centers for Disease Control and Prevention warned on May 9, 1997, that a woman who died in October, 1996 in Cumberland County, Kentucky and a man who died in December, 1996 in Missoula County, Montana were both infected with a rabies strain found in silver-haired bats; although bats were found living in the chimney of the woman's home and near the man's place of employment, neither victim could remember having had any contact with them. This inability to recognize a potential infection, in contrast to a bite from a dog or raccoon, leads to a lack of proper prophylactic treatment, and is the cause of the high mortality rate for bat bites.

In case of an attack by a possibly rabid non-human, most states in the United States allow the killing of the attacker. Because a rabies diagnosis requires that the brain tissue be preserved, it is recommended that rabid non-humans are not to be shot in the head.

Australia is one of the few regions where rabies has never been introduced. However, the Australian Bat Lyssavirus occurs normally in both insectivorous and fruit eating bats (flying foxes) from most mainland states. Scientists believe it is present in bat populations throughout the range of flying foxes in Australia.

Many territories, such as the United Kingdom, Ireland, Hawaii, Mauritius and Guam, are free of rabies (although there may be a very low prevalence of rabies among bats in the UK; see below).

Recently publicized cases

Transmission by bite

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

The United Kingdom, which has stringent regulations on the importation of non-human animals, had also been believed to be entirely free from rabies until 1996 when a single Daubenton's bat was found to be infected with a rabies-like virus usually found only in bats – European Bat Lyssavirus 2 (EBL2). There were no more known cases in the British Isles until September 2002 when another Daubenton's bat tested positive for EBL2 in Lancashire. A bat conservationist who was bitten by the infected bat received post-exposure treatment and did not develop rabies.

Then in November 2002 David McRae, a Scottish bat conservationist from Guthrie, Angus who was believed to have been bitten by a bat, became the first human to contract rabies in the United Kingdom since 1902. He died from the disease on November 24 2002.

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

In November 2004, Jeanna Giese, a fifteen-year old girl from Fond du Lac, Wisconsin, became one of only six humans known to have survived rabies after the onset of symptoms, and the first known instance of a human surviving rabies without vaccine treatment. All of the other five received vaccination before symptoms developed. Giese's disease was already too far progressed for the vaccine to help, and she was considered too weak to tolerate it. Doctors at the Children's Hospital of Wisconsin in Wauwatosa, a suburb of Milwaukee, achieved her survival with an experimental treatment that involved putting the girl into a drug-induced coma, and administering a cocktail of antiviral drugs. Giese had symptoms of full-blown rabies when she sought medical help, thirty-seven days after being bitten by a bat. Her family did not seek treatment at the time because the bat seemed healthy. Jeanna regained her weight, strength, and coordination while in the hospital. She was released from the Children's Hospital of Wisconsin on January 1, 2005.

On May 12, 2006 Harris County Health Department officials reported that a teenage boy, Zach Jones, in Houston, Texas had died of rabies after a bat flew in his bedroom while he took a nap and somehow brushed itself upon the boy's skin, allowing Jones to feel it as he woke up. He died at Texas Children's Hospital after an attempt to cure the disease through a drug-induced coma, similar to that of Jeanna Giese.

On August 6, 2006, 950 Girl Scouts were urged to receive rabies shots by the Girl Scouts of America. The nine hundred and fifty girls had attended a camp in Virginia in July, and had reported seeing bats in their cabins. Even though infections were relatively unlikely, the G.S.A. offered to pay for the shots, at a cost of nearly two million dollars. The Centers for Disease Control reports 27 cases of human rabies caused by the bat variant rabies virus in the United States from 1990 to 2002.

Transmission through organ transplants

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

Infections by corneal transplant have been reported in Thailand (2 cases), India (2 cases), Iran (2 cases), the United States (1 case), and France (1 case). Details of two further cases of infection resulting from corneal transplants were described in 1996.

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. There are bats near the donor's home, but he did not mention having been bitten. 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. 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 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.)"

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." The tragedy inspired an episode in the American TV show 'Scrubs'.

Transport of pet animals between countries

Rabies is endemic to many parts of the world, and one of the reasons given for quarantine periods in international animal transport has been to try to keep the disease out of uninfected regions. However, most developed countries, pioneered by Sweden, now allow unencumbered travel between their territories for pet animals that have demonstrated an adequate immune response to rabies vaccination.

Such countries may limit movement to animals from countries where rabies is considered to be under control in pet animals. There are various lists of such countries. The United Kingdom has developed a list, and France has a rather different list, said to be based on a list of the Office International des Epizooties (OIE). The European Union has a harmonised list. No list of rabies-free countries is readily available from OIE.

However, the recent spread of rabies in the northeastern United States and further may cause a restrengthening of precautions against movement of possibly rabid animals between countries.

Rabies and domestic skunks in the United States

There is currently no USDA-approved vaccine for the strain of rabies that afflicts skunks. When cases are reported of pet skunks biting a human, the animals are frequently killed in order to be tested for rabies.

Humans exposed to the rabies virus must begin post-exposure prophylaxis before the disease can progress to the central nervous system. For this reason, it is necessary to determine whether the animal, in fact, has rabies as quickly as possible. Without a definitive quarantine period in place for skunks, quarantining the animals is not advised as there is no way of knowing how long it may take the animal to show symptoms. Euthanasia of the skunk is recommended and the brain is then tested for presence of rabies virus.

Skunk owners have recently organized to campaign for USDA approval of both a vaccine and an officially recommended quarantine period for skunks in the United States.

See also

• Rabies in dogs
• Australian Bat Lyssavirus, a virus very similar to rabies that responds to rabies treatments.
• Cujo, a Stephen King novel (and film) about a mother and son being terrorized by a rabid dog.
• Old Yeller novel/film about a frontier dog infected by a rabid wolf.
• Rage, a 1966 film in which an alcoholic doctor (Glenn Ford) suffers a rabies infection in a Mexican village and must race across the desert–and against time–for the needed antidote that will save his life.
• Scrubs Season 5 Episode 20 (My Lunch) about 3 transplant patients who receive organs from a donor believed to have died of a cocaine overdose and subsequently found to have rabies, in a story reminiscent of the real-life Texarkana donor described above.
• 28 Days Later, a film in which a designer virus based on Rabies is created called Rage that creates fast and deadly zombie like symptoms

References

1. Rodney E. Willoughby, Jr., M.D. (2005-06-16). "Survival after Treatment of Rabies with Induction of Coma". New England Journal of Medicine. 352 (24): 2508–2514. PMID 15958806. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: multiple names: authors list (link)
2. "Rabies vaccine". WHO - Immunization, Vaccines and Biologicals. Retrieved 2006-04-20.
3. The Guardian/Jonathan Watts, "One-dog policy to fight rabies in China", November 9, 2006
4. Google News "One-dog policy", retrieved on Nov. 18, 2006
5. "Compendium of animal rabies prevention and control, 2006". MMWR Recomm Rep. 55 (RR-5): 1–8. 2006. Fulltext.
6. Nettles VF, Shaddock JH, Sikes RK, Reyes CR (1979). "Rabies in translocated raccoons". Am J Public Health. 69 (6): 601–2. PMID 443502.{{cite journal}}: CS1 maint: multiple names: authors list (link)
7. Dietzschold, B, Proniak, M (2003). "First Human Death Associated with Raccoon Rabies --- Virginia, 2003". Morbidity and Mortality Weekly Report. 52 (45). Centers for Disease Control: 1102–1103. Retrieved 2006-06-30.{{cite journal}}: CS1 maint: multiple names: authors list (link)
8. ^ Krebs JW, Strine TW, Smith JS, Noah DL, Rupprecht CE, Childs JE (1996). "Rabies surveillance in the United States during 1995". J Am Vet Med Assoc. 209 (12): 2031–44. PMID 8960176.{{cite journal}}: CS1 maint: multiple names: authors list (link)
9. "Rabies Survellance". Centers for Disease Control. 2003. Retrieved 2006-11-10.
10. Javadi MA, Fayaz A, Mirdehghan SA, Ainollahi B (1996). "Transmission of rabies by corneal graft". Cornea. 15 (4): 431–3. PMID 8776570.{{cite journal}}: CS1 maint: multiple names: authors list (link)
11. CDC (1980). "Human-to-human transmission of rabies via a corneal transplant -- France". MMWR. 29: 25–6.
12. "Investigation of rabies infections in organ donor and transplant recipients--Alabama, Arkansas, Oklahoma, and Texas, 2004". MMWR Morb Mortal Wkly Rep. 53 (26): 586–9. 2004. PMID 15241303.
13. "Update: investigation of rabies infections in organ donor and transplant recipients--Alabama, Arkansas, Oklahoma, and Texas, 2004". MMWR Morb Mortal Wkly Rep. 53 (27): 615–6. 2004. PMID 15254455.
14. Srinivasan A, Burton EC, Kuehnert MJ, Rupprecht C, Sutker WL, Ksiazek TG, Paddock CD, Guarner J, Shieh WJ, Goldsmith C, Hanlon CA, Zoretic J, Fischbach B, Niezgoda M, El-Feky WH, Orciari L, Sanchez EQ, Likos A, Klintmalm GB, Cardo D, LeDuc J, Chamberland ME, Jernigan DB, Zaki SR (2005). "Transmission of rabies virus from an organ donor to four transplant recipients". N Engl J Med. 352 (11): 1103–11. PMID 15784663.{{cite journal}}: CS1 maint: multiple names: authors list (link)
15. Reynolds G (2005). "Will Any Organ Do?". The New York Times Magazine (10 July): –.{{cite journal}}: CS1 maint: extra punctuation (link)

• Waterman, James A. 1965. "The History of the Outbreak of Paralytic Rabies in Trinidad Transmitted by Bats to Human Beings and the Lower Animals from 1925." The Caribbean Medical Journal, Vol. XXVI, Nos. 1-4, pp. 164-169.

External links

• History of Rabies in Los Angeles
• Rabies Vaccine- Information on causes and treatment

Sources

• Manbir Online
• CNN News report of CDC news release - July 1, 2004.
• Associated Press report: Families of rabies transplant victims react to deaths - July 3, 2004
• BBC News Europe Report: Romanian killer bear had rabies - 19 October, 2004.
• First Unvaccinated Rabies Survivor Goes Home - January 3, 2005

Other links

• Centers for Disease Control and Prevention
• World Health Organization factsheet on Rabies
• World Health Organization factsheet on Rabies vaccine
• Rules for importing pets to the United Kingdom
• A Rabies-Free World, Inc. - NPO dedicated to fighting rabies worldwide
• Rules for importing pets to the European Union
• Rules for importing pets to the European Union Q&A
• Aspen Skunk Rabies Research
• "When Raccoons Attack" from Field & Stream Online
• “Only Known Unvaccinated Rabies Survivor Thrives” (USA Today) Progress report on the one known survivor of rabies

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