Rabies

Rabies (. From rabies, "madness") is a viral disease that causes acute encephalitis (inflammation of the brain) in warm-blooded animals. It is zoonotic (i.e., transmitted by animals), 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. 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. Finally, the patient may experience periods of mania and lethargy, eventually leading to coma. The primary cause of death is usually respiratory insufficiency. Worldwide, roughly 97% of rabies cases come from dog bites. In the United States, however, animal control and vaccination programs have effectively eliminated domestic dogs as reservoirs of rabies. In several countries, including Australia, Japan, and the United Kingdom, rabies carried by animals that live on the ground has been eradicated entirely. Concerns exist about airborne and mixed-habitat animals including bats. A small number of bats of three species in the UK and in some other countries have been found to have European Bat Lyssavirus 1 and European Bat Lyssavirus 2. The symptoms of these viruses are similar to those of rabies and so the viruses are both known as bat rabies.

The economic impact is also substantial, as rabies is a significant cause of death of livestock in some countries.

Signs and symptoms
The period between infection and the first flu-like symptoms is normallly 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. 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, in which the patient 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.

Death almost invariably results two to ten days after first symptoms. In 2005, the first patient was treated with the Milwaukee protocol, and Jeanna Giese became the first person ever recorded to survive rabies without receiving successful post-exposure prophylaxis. An intention to treat analysis has since found that this protocol has a survival rate of about 8%. The results of this study are, however, under serious contention and clinical rabies should still be regarded as incurable at present.

Virology


The 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 nm and a cross-sectional diameter of about 75 nm. These viruses are enveloped and have a single-stranded RNA genome with negative-sense. The genetic information is packaged 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).

From the point of entry, the virus is neurotropic, traveling quickly along the neural pathways into the central nervous system (CNS), and then further into other organs. The salivary glands receive high concentrations of the virus, thus allowing further transmission.

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. 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. If possible, the animal from which the bite was received should also be examined for rabies.

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 (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. Likewise, 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. 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 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.

Prevention
All 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. Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines. The human diploid cell rabies vaccine was started in 1967; however, a new and less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available. A recombinant vaccine called V-RG has been successfully used in Belgium, France, Germany, and the United States to prevent outbreaks of rabies in wildlife. Currently pre-exposure immunization has been used in both human and non-human populations, whereas in many jurisdictions domesticated animals are required to be vaccinated.

In the USA, since the widespread vaccination of domestic dogs and cats and the development of effective human vaccines and immunoglobulin treatments, the number of recorded deaths from rabies has dropped from one hundred or more annually in the early 20th century, to 1–2 per year, mostly caused by bat bites, which may go unnoticed by the victim and hence untreated.

The Missouri Dept. of Health and Senior Services Communicable Disease Surveillance 2007 Annual Report states that the following can help reduce the risk of exposure to rabies :
 * Vaccinating dogs, cats, and ferrets against rabies
 * Keeping pets under supervision
 * Not handling wild animals or strays
 * Contacting an animal control officer, if you see a wild animal or a stray, especially if the animal is acting strangely.
 * Washing the wound with soap and water between 10 and 15 minutes, if you do get bitten by an animal, and contacting your healthcare provider to see whether you need rabies post-exposure prophylaxis.
 * 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.

Post-exposure prophylaxis
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. 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."

In the United States, 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. The immunoglobulin dose should not exceed 20 units per kilogram body weight. HRIG is very 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. 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 WHO ID (intradermal) vaccination regimens.

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. However, recent studies have further confirmed the wisdom of maintaining the current protocol of precautionary administering of PEP in cases where a child or mentally compromised individual has been left alone with a bat, especially in sleep areas, where a bite or exposure may occur while the victim is asleep and unaware or awake and unaware that a bite occurred. This is illustrated by the September 2000 case of a nine-year-old boy from Quebec who died from rabies three weeks after being in the presence of a sick bat, even though there was no apparent report of a bite, as shown in the following conclusion made by the doctors involved in the case: Despite recent criticism (45), the dramatic circumstances surrounding our patient's history, as well as increasingly frequent reports of human rabies contracted in North America, support the current Canadian guidelines that state that RPEP [PEP] is appropriate in cases where a significant contact with a bat cannot be excluded (45). The notion that a bite or an overt break in the skin needs to be seen or felt for rabies to be transmitted by a bat is a myth in many cases.

It is highly recommended that PEP be administered as soon as possible. Begun with little or no delay, PEP is 100% effective against rabies. In the case in which there has been a significant delay in administering PEP, the treatment should be administered regardless of that delay, as it may still be effective. If there has been a delay between exposure and attempts at treatment, such that the possibility exists that the virus has already penetrated the nervous system, the possibility exists that amputation of the affected limb might thwart rabies, if the bite or exposure was on an arm or leg. This treatment should be combined with an intensive PEP regimen.

Blood-brain barrier
During lethal rabies infection of mice, the blood-brain barrier (BBB) does not allow anti-viral immune cells to enter the brain, the primary site of rabies virus replication. This aspect contributes to the pathogenicity of the virus and artificially increasing BBB permeability promotes viral clearance. Opening the BBB during rabies infection has been suggested as a possible novel approach to treating the disease, even though no attempts have yet been made to determine whether or not this treatment could be successful.

Induced coma
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. She survived with almost no permanent sequelae and as of 2009 was starting her third year of university studies.

Giese's treatment regimen became known as the "Milwaukee protocol", which has since undergone revision (the second version omits the use of ribavirin). There were 2 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 2 survivors. The anesthetic drug ketamine has shown the potential for rabies virus inhibition in rats, and is used as part of the Milwaukee protocol.

On April 10, 2008 in Cali, Colombia, an eleven-year-old boy was reported to survive rabies and the induced coma without noticeable brain damage.

On June 12, 2011, Precious Reynolds, an eight-year-old girl from Humboldt County, California, became the third reported person in the United States to have recovered from rabies without receiving post-exposure prophylaxis.

Prognosis
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. There are only six known cases of a person surviving symptomatic rabies, and only one known case of survival in which the patient received no rabies-specific treatment either before or after illness onset.

Survival data using the Milwaukee protocol are available from the rabies registry.

Transmission
Any warm-blooded animal (including humans) may become infected with the rabies virus and develop symptoms (although birds have only been known to be experimentally infected ). Indeed the virus has even been adapted to grow in cells of poikilothermic ("cold-blooded") vertebrates. Most animals can be infected by the virus and can transmit the disease to humans. Infected bats, monkeys, raccoons, foxes, skunks, cattle, wolves, coyotes, dogs, mongoose (normally yellow mongoose) 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. The Virginia opossum is resistant but not immune to rabies.

The virus is usually present in the nerves and saliva of a symptomatic rabid animal. 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.

Transmission between humans is extremely rare. A few cases have been recorded through transplant surgery.

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. 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.

Prevalence
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. In some countries, like those in western Europe and Oceania, rabies is considered to be prevalent among bat populations only.

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.

There are an estimated 55,000 human deaths annually from rabies worldwide, with about 31,000 in Asia, and 24,000 in Africa. 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. India has been reported as having the highest rate of human rabies in the world, primarily because of stray dogs. , Vietnam had the second-highest rate, followed by Thailand; in these countries too the virus is primarily transmitted through canines (feral dogs and other wild canine species).

Rabies was once rare in the United States outside the Southern states, but raccoons in the mid-Atlantic and northeastern United States have been suffering from a rabies epidemic, dating from the 1970s, which was moving westward into Ohio. In the midwestern United States, skunks are the primary carriers of rabies, comprising 134 of the 237 documented non-human cases.

According to the Journal of the American Veterinary Medical Association (JAVMA), the state of Missouri had a total of 66 documented cases of rabies. Of the 66 cases, 50 were bats, 15 were skunks, and one domestic cat. This contradicts the CDC finding that in the midwest most rabies cases are found in skunks. Surveying other states in the midwest (including Illinois, Iowa, Kansas, North and South Dakota, Nebraska, Wisconsin, Minnesota, Michigan, Ohio, and Indiana), the JAVMA found that, out of 671 confirmed rabies cases, 352 cases were bats, 223 were skunks, and the remaining cases were other animals. Therefore, between 1996 and 2009, there has been a relative decrease in the US midwest in the prevalence of skunks with rabies, and an increase in the prevalence of bats with rabies.

Etymology
The term is derived from the Latin rabies, "madness". 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.

Impact
Because of its potentially violent nature, rabies has been known since c.2000 B.C. 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.

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; however, this gave Louis Pasteur ample opportunity to test post-exposure treatments from 1885.

In other animals
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.