Rabies (pronounced /ˈreɪbiːz/. From Latin: rabies, "madness") is a viral disease that causes acute encephalitis (inflammation of the brain) in warm-blooded animals.[1] It is zoonotic (i.e., transmissible from animals to humans), most commonly by a bite from an infected animal. For a human, rabies is almost invariably fatal if post-exposure prophylaxis is not administered prior to the onset of severe symptoms. The rabies virus infects the central nervous system, ultimately causing disease in the brain and death.
The rabies virus travels to the brain by following the peripheral nerves. The incubation period of the disease is usually a few months in humans, depending on the distance the virus must travel to reach the central nervous system.[2] Once the rabies virus reaches the central nervous system and symptoms begin to show, the infection is effectively untreatable and usually fatal within days.
Early-stage symptoms of rabies are malaise, headache and fever, progressing to acute pain, violent movements, uncontrolled excitement, depression, and hydrophobia.[1] Finally, the patient may experience periods of mania and lethargy, eventually leading to coma. The primary cause of death is usually respiratory insufficiency.[2]
Overall, roughly 97% of human rabies cases result from dog bites.[3] In the US, animal control and vaccination programs have effectively eliminated domestic dogs as reservoirs of rabies.[4] In several countries, including Australia and Japan, rabies carried by terrestrial animals has been eliminated entirely.[5] The rabies virus was eliminated from the UK early in the 20th century.[6]
Patient with rabies, 1959
The period between infection and the first flu-like symptoms is typically two to twelve weeks, but incubation periods as short as four days and longer than six years have been documented, depending on the location and severity of the inoculating wound and the amount of virus introduced. Soon after, the symptoms expand to slight or partial paralysis, anxiety, insomnia, confusion, agitation, abnormal behavior, paranoia, terror, hallucinations, progressing to delirium.[2][7] Rabies has been called hydrophobia because victims, locally paralyzed and unable to swallow, have been known to become agitated at the sight of water.[8]
Death almost invariably results two to ten days after first symptoms. Once symptoms have presented, survival is rare, even with the administration of proper and intensive care.[9] In 2005 Jeanna Giese, the first patient treated with the Milwaukee protocol,[10] became the first person ever recorded to survive rabies without receiving successful postexposure prophylaxis. An intention to treat analysis has since found that this protocol has a survival rate of about eight percent.[11]
Main article:
Rabies virusThe rabies virus is the type species of the Lyssavirus genus, in the family Rhabdoviridae, order Mononegavirales. Lyssaviruses have helical symmetry, with a length of about 180 nanometres and a cross-section diametre of about 75 nanometres.[1] These viruses are enveloped and have a single-stranded RNA genome with negative-sense. The genetic information is packed as a ribonucleoprotein complex in which RNA is tightly bound by the viral nucleoprotein. The RNA genome of the virus encodes five genes whose order is highly conserved: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and the viral RNA polymerase (L).[12]
Once within a muscle or nerve cell, the virus undergoes replication. The trimeric spikes on the exterior of the membrane of the virus interact with a specific cell receptor, the most likely one being the acetylcholine receptor. The cellular membrane pinches in a procession known as pinocytosis and allows entry of the virus into the cell by way of an endosome. The virus then utilizes the acidic environment of that endosome and binds to its membrane simultaneously releasing its five proteins and single strand RNA into the cytoplasm. The L protein then transcribes five mRNA strands and a positive strand of RNA all from the original negative strand RNA using free nucleotides in the cytoplasm. These five mRNA strands are then translated into their corresponding proteins (P, L, N, G and M proteins) at free ribosomes in the cytoplasm. Some proteins require posttranslative modifications. For example, the G protein travels through the rough endoplasmic reticulum where it undergoes further folding, and is then transported to the Golgi Apparatus where a sugar group is added to it (glycosylation). Where there are enough proteins, the viral polymerase will begin to synthesize new negative strands of RNA from the template of the positive strand RNA. These negative strands will then form complexes with the N, P, L and M proteins and then travel to the inner membrane of the cell where a G protein has embedded itself in the membrane. The G protein then coils around the N-P-L-M complex of proteins taking some of the host cell membrane with it which will form the new outer envelope of the virus particle. The virus then buds from the cell.[13]
From the point of entry, the virus is neurotropic, traveling quickly along the neural pathways into the central nervous system (CNS), and then to other organs.[2] The salivary glands receive high concentrations of the virus, thus allowing further transmission.
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.[14] It is also possible to make the diagnosis from saliva, urine and cerebrospinal fluid samples, but this is not as sensitive. Cerebral inclusion bodies called Negri bodies are 100% diagnostic for rabies infection, but are found in only about 80% of cases.[1] If possible, the animal from which the bite was received should also be examined for rabies.[15]
The differential diagnosis in a case of suspected human rabies may initially include any cause of encephalitis, in particular infection with viruses such as herpesviruses, enteroviruses, and arboviruses such as West Nile virus. The most important viruses to rule out are herpes simplex virus type one, varicella-zoster virus, and (less commonly) enteroviruses, including coxsackieviruses, echoviruses, polioviruses, and human enteroviruses 68 to 71.[16]
New causes of viral encephalitis are also possible, as was evidenced by the 1999 outbreak in Malaysia of three hundred cases of encephalitis with a mortality rate of forty per cent caused by Nipah virus, a newly recognized paramyxovirus.[17] Likewise, well-known viruses may be introduced into new locales, as is illustrated by the recent out-break of encephalitis due to West Nile virus in the eastern US.[18] Epidemiologic factors such as season, geographic location, and the patient's age, travel history, and possible exposure to bites, rodents, and ticks may help direct the diagnosis.
Cheaper rabies diagnosis will become possible for low-income settings: accurate rabies diagnosis can be done at a tenth of the cost of traditional testing using basic light microscopy techniques.[19]
Main article:
Rabies vaccineAll human cases of rabies were fatal until a vaccine was developed in 1885 by Louis Pasteur and Émile Roux. Their original vaccine was harvested from infected rabbits, from which the virus in the nerve tissue was weakened by allowing it to dry for five to ten days.[20] Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines.[21] The human diploid cell rabies vaccine was started in 1967; a new and less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available.[15] A recombinant vaccine called V-RG has been successfully used in Belgium, France, Germany, and the US to prevent outbreaks of rabies in undomesticated animals.[22] Currently preexposure immunization has been used in both human and nonhuman populations, where as in many jurisdictions domesticated animals are required to be vaccinated.[23]
In the US, since the widely spread vaccination of domestic dogs and cats and the development of effective human vaccines and immunoglobulin treatments, the number of recorded human deaths from rabies has dropped from one hundred or more annually in the early 20th century, to one to two per year, mostly caused by bat bites, which may go unnoted by the victim and hence untreated.[4]
The Missouri Department of Health and Senior Services Communicable Disease Surveillance 2007 Annual Report states that the following can help reduce the risk of exposure to rabies:[24]
- Vaccinating dogs, cats, rabbits, and ferrets against rabies
- Keeping pets under supervision
- Not handling wild animals or strays
- Contacting an animal control officer upon observing a wild animal or a stray, especially if the animal is acting strangely.
- Washing the wound with soap and water for 10 to 15 minutes, if you do get bitten by an animal, and contacting your healthcare provider to determine if post-exposure prophylaxis is required.
- Getting pets spayed or neutered. Pets that are sterile are less likely to leave home, become strays, and reproduce more stray animals.
September 28 is World Rabies Day, which promotes information on, and prevention and elimination of the disease.[25]
Treatment after exposure, known as post-exposure prophylaxis (PEP), is highly successful in preventing the disease if administered promptly, in general within ten days of infection.[1] Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is very effective in 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. Exposed mucous membranes such as eyes, nose or mouth should be flushed well with water."[26]
In the US, the Centers for Disease Control and Prevention (CDC) recommend patients receive one dose of human rabies immunoglobulin (HRIG) and four doses of rabies vaccine over a fourteen-day period.[27] The immunoglobulin dose should not exceed 20 units per kilogram body weight. HRIG is expensive and constitutes the vast majority of the cost of post-exposure treatment, ranging as high as several thousand dollars. As much as possible of this dose should be infiltrated around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site.[13] The first dose of rabies vaccine is given as soon as possible after exposure, with additional doses on days three, seven and fourteen after the first. Patients who have previously received pre-exposure vaccination do not receive the immunoglobulin, only the post-exposure vaccinations on day 0 and 2.
Modern cell-based vaccines are similar to flu shots in terms of pain and side-effects. The old nerve-tissue-based vaccinations that require multiple painful injections into the abdomen with a large needle are cheap, but are being phased out and replaced by affordable World Health Organization (WHO) intradermal (ID) vaccination regimens.[15]
Intramuscular vaccination should be given into the deltoid, not gluteal area, which has been associated with vaccination failure due to injection into fat rather than muscle. In infants, the lateral thigh is used as for routine childhood vaccinations.
Awakening to find a bat in the room, or finding a bat in the room of a previously unattended child or mentally disabled or intoxicated person, is regarded as an indication for post-exposure prophylaxis. The recommendation for the precautionary use of post-exposure prophylaxis in occult bat encounters where there is no recognized contact has been questioned in the medical literature, based on a cost-benefit analysis.[28] However, a 2002 study has supported the protocol of precautionary administering of PEP where a child or mentally compromised individual has been alone with a bat, especially in sleep areas, where a bite or exposure may occur without the victim being aware.[29] Begun with little or no delay, PEP is 100% effective against rabies.[10] In the case in which there has been a significant delay in administering PEP, the treatment should be administered regardless, as it may still be effective.[13]
There is evidence that artificially increasing the permeability of the blood brain barrier, which normally does not allow most immune cells across, promotes viral clearance.[30][31]
In 2004, American teenager Jeanna Giese survived an infection of rabies unvaccinated. She was placed into an induced coma upon onset of symptoms and given ketamine, midazolam, ribavirin, and amantadine. Her doctors administered treatment based on the hypothesis that detrimental effects of rabies were caused by temporary dysfunctions in the brain and could be avoided by inducing a temporary partial halt in brain function that would protect the brain from damage while giving the immune system time to defeat the virus. After thirty-one days of isolation and seventy-six days of hospitalization, Giese was released from the hospital.[32] She survived with almost no permanent after-effects and as of 2009 was starting her third year of university studies.[33]
Giese's treatment regimen became known as the "Milwaukee protocol", which has since undergone revision with the second version omits the use of ribavirin. There were two survivors out of 25 patients treated under the first protocol. A further 10 patients have been treated under the revised protocol and there have been a further two survivors.[11] The anesthetic drug ketamine has shown the potential for rabies virus inhibition in rats,[34] and is used as part of the Milwaukee protocol.
On April 10, 2008 in Cali, Colombia, a boy of 11 was reported to survive rabies and the induced coma without noticeable brain damage.[35]
On June 12, 2011, Precious Reynolds, an eight-year-old girl from Humboldt County, California, became the third reported person in the world and the second in the United States to have recovered from rabies without receiving post-exposure prophylaxis.[36]
Treatment after exposure (receiving the vaccines), known as post-exposure prophylaxis (PEP), is highly successful in preventing the disease if administered promptly, in general within ten days of infection. Begun with little or no delay, PEP is 100% effective against rabies.[10] In the case in which there has been a significant delay in administering PEP, the treatment still has a chance of success.[13]
In unvaccinated humans, rabies is usually fatal after neurological symptoms have developed, but prompt post-exposure vaccination may prevent the virus from progressing. Rabies kills around 55,000 people a year, mostly in Asia and Africa.[37]
Survival data using the Milwaukee protocol are available from the rabies registry.[38] As of 2011, seven people have been saved by this induced coma treatment.
Rabies-free countries (in green) as of 2010
[update]
Any warm-blooded animal including humans may become infected with the rabies virus and develop symptoms, although birds have only been known to be infected in experiments.[39] The virus has even been adapted to grow in cells of poikilothermic ("cold-blooded") vertebrates.[40][41] Most animals can be infected by the virus and can transmit the disease to humans. Infected bats,[42][43] monkeys, raccoons, foxes, skunks, cattle, wolves, coyotes, dogs, mongoose (normally yellow mongoose)[44] or cats present the greatest risk to humans. Rabies may also spread through exposure to infected domestic farm animals, groundhogs, weasels, bears and other wild carnivores. Small rodents such as squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, and mice and lagomorphs like rabbits and hares are almost never found to be infected with rabies and are not known to transmit rabies to humans.[45] The Virginia opossum is resistant but not immune to rabies.[46]
The virus is usually present in the nerves and saliva of a symptomatic rabid animal.[47][48] The route of infection is usually, but not always, by a bite. In many cases the infected animal is exceptionally aggressive, may attack without provocation, and exhibits otherwise-uncharacteristic behavior.[49]
Transmission between humans is extremely rare. A few cases have been recorded through transplant surgery.[50]
After a typical human infection by bite, the virus enters the peripheral nervous system. It then travels along the nerves toward the central nervous system.[51] During this phase, the virus cannot be easily detected within the host, and vaccination may still confer cell-mediated immunity to prevent symptomatic rabies. When the virus reaches the brain, it rapidly causes encephalitis. This is called the prodromal phase, and is the beginning of the symptoms. Once the patient becomes symptomatic, treatment is almost never effective and mortality is over 99%. Rabies may also inflame the spinal cord, producing transverse myelitis.[52][53]
The rabies virus survives in widespread, varied, rural fauna reservoirs. It is present in the animal populations of almost every country in the world, except in Australia and New Zealand.[54] Australian Bat Lyssavirus (ABLV) discovered in 1996 is similar to rabies, and is believed to be prevalent in native bat populations. In some countries, like those in western Europe and Oceania, rabies is considered to be prevalent among bat populations only.[citation needed]
In Asia, parts of the Americas, 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, a practice that has successfully reduced rabies in rural areas of Canada, France, and the USA. In Montréal, Canada, baits are successfully used on raccoons in the Mont-Royal Park area. Vaccination campaigns may be expensive, and cost-benefit analysis suggests that baits may be a cost effective method of control.[55]
There are an estimated 55,000 human deaths annually from rabies worldwide, with about 31,000 in Asia, and 24,000 in Africa.[37] One of the sources of recent flourishing of rabies in East Asia is the pet boom. China introduced the "one-dog policy" in the city of Beijing in November 2006 to control the problem.[56] India has been reported as having the highest rate of human rabies in the world, primarily because of stray dogs.[57] As of 2007[update], Vietnam had the second-highest rate, followed by Thailand; in these countries the virus is primarily transmitted through canines (feral dogs and other wild canine species).[58]
Rabies is common among wild animals in the US. Bats, raccoons, skunks and foxes account for almost all reported cases (98% in 2009). Rabid bats are found in all 48 contiguous states. Other reservoirs are more limited geographically: for example, the raccoon rabies virus variant is only found in a relatively narrow band along the East Coast. Due to a high public awareness of the virus, efforts at vaccination of domestic animals and curtailment of feral populations, and availability of post-exposure prophylaxis, incidents of rabies in humans are very rare. There was a total of 45 cases of the disease in the country in 1995-2010; of these, 9 are thought to have been acquired abroad. Almost all domestically acquired cases are attributed to bat bites.[59]
A woodcut from the Middle Ages showing a rabid dog
The term is derived from the Latin rabies, "madness".[60] This, in turn, may be related to the Sanskrit rabhas, "to do violence". The Greeks derived the word "lyssa", from "lud" or "violent"; this root is used in the name of the genus of rabies Lyssavirus.[61]
Because of its potentially violent nature, rabies has been known since c.2000 B.C.[62] The first written record of rabies is in the Mesopotamian Codex of Eshnunna (ca. 1930 BC), which dictates that the owner of a dog showing symptoms of rabies should take preventive measure against bites. If another person was bitten by a rabid dog and later died, the owner was heavily fined.[63]
Rabies was considered a scourge for its prevalence in the 19th century. In France and Belgium, where Saint Hubert was venerated, the "St Hubert's Key" was heated and applied to cauterize the wound; by an application of magical thinking, dogs were branded with the key in hopes of protecting them from rabies. Fear of rabies related to methods of transmissions was almost irrational;[61] however, this gave Louis Pasteur ample opportunity to test post-exposure treatments from 1885.[64] In ancient medical times, the attachment of the tongue (the frenum linguae, a mucous membrane) was cut and removed as this is where rabies was thought to originate. This practice ceased with the discovery of the actual cause of rabies.[65]
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 for the tendency of the affected animal 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 owing 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.[66]
Rabies has the advantage over other pseudotyping methods for gene delivery in that the cell targeting (tissue tropism) is more specific for difficult to reach sites such as the central nervous system without invasive delivery methods as well as capable of retrograde tracing (i.e. going against the flow of information at synapses) in neuronal circuits.[67]
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