Rabies

The name rabies is derived from the Latin , meaning 'madness'. The Greek word (, 'madness'), derived either from a feminine form of (, 'wolf') or from the Proto-Indo-European root ('light'), is used in the genus name of the rabies virus, Lyssavirus. == Signs and symptoms ==

The incubation period between infection and the first symptoms is typically one to three months in humans. As rabies progresses and causes inflammation of the brain and meninges, symptoms can include slight or partial paralysis, anxiety, insomnia, confusion, agitation, abnormal behavior, paranoia, terror, and hallucinations. Rabies has also occasionally been referred to as hydrophobia ("fear of water") throughout its history. It refers to a set of symptoms in the later stages of an infection in which the person has difficulty swallowing, shows panic when presented with liquids to drink, and cannot quench their thirst. Saliva production is greatly increased, and attempts to drink, or even the intention or suggestion of drinking, may cause excruciatingly painful spasms of the muscles in the throat and larynx. Since the infected individual cannot swallow saliva and water, the virus has a much higher chance of being transmitted, because it multiplies and accumulates in the salivary glands and is transmitted through biting. Hydrophobia is commonly associated with furious rabies, which affects 80% of rabies-infected people. This form of rabies causes irrational aggression in the host, which aids in the spreading of the virus through animal bites; a "foaming at the mouth" effect, caused by the accumulation of saliva, is also commonly associated with rabies in the public perception and in popular culture. The remaining 20% may experience a paralytic form of rabies that is marked by muscle weakness, loss of sensation, and paralysis; this form of rabies does not usually cause fear of water. ==Cause==

File:Electron microscope image of rabies virus.jpg|An electron microscope image of the rabies virus File:Rabies Virus EM PHIL 1876.JPG|TEM micrograph with numerous rabies virions (small, dark grey, rodlike particles) and Negri bodies (the larger pathognomonic cellular inclusions of rabies infection) Rabies is caused by a number of lyssaviruses including the rabies virus and Australian bat lyssavirus. The rabies virus is the type species of the Lyssavirus genus, in the family Rhabdoviridae, order Mononegavirales. Lyssavirions have helical symmetry, with a length of about 180 nm and a cross-section of about 75 nm. These virions 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). To enter cells, 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 uses the acidic environment, which is necessary, of that endosome and binds to its membrane simultaneously, releasing its five proteins and single-strand RNA into the cytoplasm. The virus then travels through the nerve cell axon via retrograde transport, as its P protein interacts with dynein, a protein present in the cytoplasm of nerve cells. Once the virus reaches the cell body it travels rapidly to the central nervous system (CNS), replicating in motor neurons and eventually reaching the brain. After the brain is infected, the virus travels centrifugally to the peripheral and autonomic nervous systems, eventually migrating to the salivary glands, where it is ready to be transmitted to the next host. == Transmission ==

All warm-blooded species, including humans, may become infected with the rabies virus. Birds were first artificially infected with rabies in 1884; however, infected birds are largely, if not wholly, asymptomatic, and recover. Some bird species have been known to develop rabies antibodies, a sign of infection, after feeding on rabies-infected mammals. The virus has adapted to grow in cells of cold-blooded vertebrates. Most animals can be infected by the virus and can transmit the disease to humans. Worldwide, about 99% of human rabies cases come from dogs. Other sources of rabies in humans include bats, monkeys, raccoons, foxes, skunks, cattle, wolves, coyotes, cats, and mongooses (normally either the small Asian mongoose or the yellow mongoose). Rabies may also spread through exposure to infected bears, domestic farm animals, groundhogs, weasels, and other wild carnivorans. However, lagomorphs, such as hares and rabbits, and small rodents, such as chipmunks, gerbils, guinea pigs, hamsters, mice, rats, and squirrels, are almost never found to be infected with rabies and are not known to transmit rabies to humans. Bites from mice, rats, or squirrels rarely require rabies prevention because these rodents are typically killed by any encounter with a larger, rabid animal, and would, therefore, not be carriers. The Virginia opossum (a marsupial, unlike the other mammals named in this paragraph, which are all eutherians/placental), has a lower internal body temperature than the rabies virus prefers and therefore is resistant but not immune to rabies. Marsupials, along with monotremes (platypuses and echidnas), typically have lower body temperatures than similarly sized eutherians. In 2024, rabies was found to be spreading in South African Cape fur seals, possibly making it the first outbreak documented in marine mammals. 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. This is an example of a viral pathogen modifying the behavior of its host to facilitate its transmission to other hosts. After a typical human infection by bite, the virus enters the peripheral nervous system. It then travels retrograde along the efferent 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, the prodromal phase, which 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. Although it is theoretically possible for humans to transmit rabies by biting, no such cases have been documented, because infected humans are usually hospitalized and precautions taken. Casual contact, such as touching a person with rabies or contact with non-infectious fluid or tissue (urine, blood, feces), does not constitute an exposure and does not require post-exposure prophylaxis. As the virus is present in sperm and vaginal secretions, it might be possible for rabies to spread through sex. There are only a small number of recorded cases of human-to-human transmission of rabies, and all occurred through organ transplants, most frequently with corneal transplantation, from infected donors. == Diagnosis ==

Rabies can be difficult to diagnose because, in the early stages, it is easily confused with other diseases or even with a simple aggressive temperament. The reference method for diagnosing rabies is the fluorescent antibody test (FAT), an immunohistochemistry procedure, which is recommended by the World Health Organization (WHO). The FAT relies on the ability of a detector molecule (usually fluorescein isothiocyanate) coupled with a rabies-specific antibody, forming a conjugate, to bind to and allow the visualisation of rabies antigen using fluorescent microscopy techniques. Microscopic analysis of samples is the only direct method that allows for the identification of rabies virus-specific antigen in a short time and at a reduced cost, irrespective of geographical origin and status of the host. It has to be regarded as the first step in diagnostic procedures for all laboratories. Autolysed samples can, however, reduce the sensitivity and specificity of the FAT. The RT PCR assays proved to be a sensitive and specific tool for routine diagnostic purposes, particularly in decomposed samples or archival specimens. The diagnosis can be reliably made from brain samples taken after death. The diagnosis can also be made from saliva, urine, and cerebrospinal fluid samples, but this is not as sensitive or reliable as brain samples. Some light microscopy techniques may also be used to diagnose rabies at a tenth of the cost of traditional fluorescence microscopy techniques, allowing identification of the disease in less-developed countries. A test for rabies, known as LN34, is easier to run on a dead animal's brain and might help determine who does and does not need post-exposure prevention. 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. == Prevention ==

Almost all human exposure to rabies was 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. Less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available. Immunization before exposure has been used in both human and nonhuman populations, where, as in many jurisdictions, domesticated animals are required to be vaccinated. The Missouri Department of Health and Senior Services Communicable Disease Surveillance 2007 Annual Report states the following can help reduce the risk of contracting rabies: • Vaccinating dogs, cats, 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 • If bitten by an animal, washing the wound with soap and water for 10 to 15 minutes and contacting a healthcare provider to determine if post-exposure prophylaxis is required 28 September is World Rabies Day, which promotes the information, prevention, and elimination of the disease. In Asia and in parts of the Americas and 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 United States. In Montreal, Quebec, Canada, baits are successfully used on raccoons in the Mount-Royal Park area. Vaccination campaigns may be expensive, but cost-benefit analysis suggests baits may be a cost-effective method of control. In Ontario, a dramatic drop in rabies was recorded when an aerial bait-vaccination campaign was launched. The number of recorded human deaths from rabies in the United States has dropped from 100 or more annually in the early 20th century to one or two per year because of widespread vaccination of domestic dogs and cats and the development of human vaccines and immunoglobulin treatments. Most deaths now result from bat bites, which may go unnoticed by the victim and hence untreated. ==Treatment==

After exposure Treatment after exposure can prevent the disease if given within 10 days. The rabies vaccine is 100% effective if given before symptoms of rabies appear. Every year, over 29 million people worldwide get vaccinated after potential exposure. While this works well, the cost is significant. In the US it is recommended people receive one dose of human rabies immunoglobulin (HRIG) and four doses of rabies vaccine over a 14-day period. HRIG is expensive and makes up most of the cost of post-exposure treatment, ranging as high as several thousand dollars. In the UK, one dose of HRIG costs the National Health Service £1,000, although this is not flagged as a "high-cost medication". A full course of vaccine costs £120–180. As much as possible of HRIG should be injected around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site. People who have previously been vaccinated against rabies do not need to receive the immunoglobulin—only the postexposure vaccinations on days 0 and 3. The side effects of modern cell-based vaccines are similar to the side effects of flu shots. The old nerve-tissue-based vaccination required multiple injections into the abdomen with a large needle but is inexpensive. It is being phased out and replaced by affordable World Health Organization intradermal-vaccination regimens. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is effective in reducing the number of viral particles. Povidone-iodine or alcohol is then recommended to reduce the virus further. 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 an indication for post-exposure prophylaxis (PEP). The recommendation for the precautionary use of PEP in bat encounters where no contact is recognized has been questioned in the medical literature, based on a cost–benefit analysis. However, a 2002 study has supported the protocol of precautionary administration 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 with the victim being unaware. Although once standard, the rabies vaccine in many countries is no longer given as a series of painful injections into the abdomen. Rather, it is given as a series of intramuscular injections into the upper arm. Fears about the pain of post-exposure prophylaxis are especially dangerous as they may prevent those who have been exposed to rabies from seeking medical attention in a timely fashion. A treatment known as the Milwaukee protocol, which involves putting people with rabies symptoms into a chemically induced coma and using antiviral medications in an attempt to protect their brain until their body has had time to produce rabies antibodies, has been occasionally used. It was initially attempted in 2004 on Jeanna Giese, a teenage girl from Wisconsin, who subsequently became the first human known to have survived rabies without receiving post-exposure prophylaxis before symptom onset. Giese did require extensive rehabilitation afterward, and her balance and neural function remained impaired. The protocol has been enacted on many rabies victims since, but has been adjudged a failure; some survivors of the acute initial phase later died of rabies. Concerns have also been raised about its monetary costs and its ethics, with a report in 2025 asserting that of the few patients who survived rabies under the Milwaukee Protocol, some may never have actually had rabies progression to the point of developing antibodies, and should thus not be counted as rabies patients which, if true, compromises the validity of some success cases. Antiviral therapy to combat the effects of rabies has also been researched; favipiravir, for example, has shown potential at inhibiting the development of encephalitis. It has been suggested that such therapy in combination with immunotherapy and neuroprotective measures could be beneficial. ==Prognosis==

Vaccination after exposure, PEP, is highly successful in preventing rabies. ==Epidemiology==

In 2010, an estimated 26,000 people died from rabies, down from 54,000 in 1990. The majority of the deaths occurred in Asia and Africa. A 2015 collaboration between the World Health Organization, World Organization of Animal Health (OIE), Food and Agriculture Organization of the United Nation (FAO), and Global Alliance for Rabies Control has a goal of eliminating deaths from rabies by 2030. India India has the highest rate of human rabies in the world, primarily because of stray dogs, whose number has greatly increased since a 2001 law forbade the killing of dogs. Effective control and treatment of rabies in India is hindered by a form of mass hysteria known as puppy pregnancy syndrome (PPS). Dog bite victims with PPS, male as well as female, become convinced that puppies are growing inside them, and often seek help from faith healers rather than medical services. An estimated 20,000 people die every year from rabies in India, more than a third of the global total. although Australian bat lyssavirus (ABLV), discovered in 1996, is a rabies-causing virus related to the rabies virus prevalent in Australian native bat populations. United States Canine-specific rabies has been eradicated in the United States, but rabies is common among wild animals, and an average of 100 dogs become infected from other wildlife each year. High public awareness of the virus, efforts at vaccination of domestic animals and curtailment of feral populations, and availability of postexposure prophylaxis have made rabies very rare in humans in the United States. From 1960 to 2018, a total of 125 such cases were reported in the United States; of them, 36 (28%) were attributed to dog bites suffered during international travel. Rabies in a feral cat (part of a colony of 20 cats) was reported from Maryland in 2025. Europe carried by bats Either no or very few cases of rabies are reported each year in Europe; cases are contracted both during travel and in Europe. In Switzerland the disease was virtually eliminated after scientists placed chicken heads laced with live attenuated vaccine in the Swiss Alps. Italy, after being declared rabies-free from 1997 to 2008, witnessed a temporary reemergence of the disease in wild animals in the Triveneto regions (Trentino-Alto Adige/Südtirol, Veneto and Friuli-Venezia Giulia) due to the spreading of an epidemic in the Balkans that also affected Austria. An extensive wild animal vaccination campaign eliminated the virus from Italy again, and it regained the rabies-free country status in 2013, the last reported case of rabies being reported in a red fox in early 2011. The United Kingdom has been free of rabies since the early 20th century except for a rabies-like virus (EBLV-2) in a few Daubenton's bats. There has been one fatal case of EBLV-2 transmission to a human. there had been six deaths from rabies transmitted abroad by dogs and cats since 2000. The last infection in the UK occurred in 1922, and the last death from indigenous rabies was in 1902. Sweden and mainland Norway have been free of rabies since 1886. Bat rabies antibodies (but not the virus) have been found in bats. On Svalbard, animals can cross the arctic ice from Greenland or Russia. In Europe there have been five documented human deaths caused by lyssaviruses carried by bats: in Ukraine (1977, species not characterised), Russia (1985, EBLV‐1), Finland (1985, EBLV‐2), the United Kingdom (2002, EBLV‐2) and France (2019, EBLV‐1). Mexico Mexico was certified by the World Health Organization as being free of dog-transmitted rabies in 2019 because no case of dog-human transmission had been recorded in two years. Asian countries Despite rabies being preventable and the many successes over the years from North America, South Korea and Western Europe, rabies remains endemic in many southern and eastern Asian countries including Cambodia, Bangladesh, Bhutan, North Korea, India, Indonesia, Myanmar, Nepal, Sri Lanka, and Thailand. Half the global rabies deaths occur in southeast Asia, approximately 26,000 per year. Much of what prevents Asia from implementing the same measures as other countries is cost. Treating wild canines is the primary means of preventing rabies; however, it costs 10 times more than treating individuals as they come with bites, and research also increases cost. As a result, India and other surrounding countries are unable to apply many preventative measures because of financial limitations. Cambodia Cambodia has approximately 800 cases of human rabies per year, making it one of the top countries in human rabies incidences. Much of this falls on their lack of animal care; Cambodia has hundreds of thousands of animals infected with rabies, another global high, yet little surveillance of said animals and few laws requiring pets and other household animals to be vaccinated. However, it is still lacking in terms of animal surveillance and treatment which leads to bleeding into surrounding countries. Thailand In 2013 human rabies was nearly eradicated in the state of Thailand after new measures were put into place requiring the vaccination of all domestic dogs as well as programs seeking to vaccinate wild dogs and large animals. However, neighboring countries unable to afford rabies control measures – Cambodia, Laos, and Myanmar – allowed infected animals to continue to pass the border and infect the Thai population, leading to ~100 cases a year. These areas around the border are called Rabies Red areas and are where Thailand continuously struggles with eradication and will do so until the surrounding countries eliminate the virus. ==History==

Rabies has been known since around 2000 BC. The first written record of rabies is in the Mesopotamian Codex of Eshnunna (), which dictates that the owner of a dog showing symptoms of rabies should take preventive measures against bites. If another person were bitten by a rabid dog and later died, the owner was heavily fined. In ancient Greece, rabies was believed to be caused by Lyssa, the spirit of mad rage. Ineffective folk remedies abounded in the medical literature of the ancient world. The physician Scribonius Largus prescribed a poultice of cloth and hyena skin; Antaeus recommended a preparation made from the skull of a hanged man. Rabies appears to have originated in the Old World: the first epizootic in the New World occurring in Boston in 1768. 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. In ancient times the attachment of the tongue (the lingual frenulum, a mucous membrane) was cut and removed, as this was where rabies was thought to originate. This practice ceased with the discovery of the actual cause of rabies. Louis Pasteur's 1885 nerve tissue vaccine was successful, and was progressively improved to reduce often severe side-effects. File:Cantigas de Santa Maria-275-5.jpg|Miniature of the Cantiga #275 depicting two monks hospitaller with rabies being carried before St. Mary of Terena File:Middle Ages rabid dog.jpg|A woodcut from the Middle Ages showing a rabid dog File:Sauvages de la Croix, François Boissier de – Dissertation sur la nature et la cause de la Rage, 1777 – BEIC 3001126.jpg|François Boissier de Sauvages de Lacroix, Della natura e causa della rabbia (Dissertation sur la nature et la cause de la Rage), 1777 File:Medieval rabies folio.jpg|alt=An ancient folio from the medieval times depicting a rabid dog biting a man. circa 1224|An Arabic folio from the medieval times depicting a rabid dog biting a man, c. 1224 ==Other animals==

Rabies is infectious to mammals; three stages of central nervous system infection are recognized. The clinical course is often shorter in animals than in humans, but result in similar symptoms and almost always death. The first stage is a one- to three-day period characterized by behavioral changes and is known as the prodromal stage. The second is the excitative stage, which lasts three to four days. This stage is often known as "furious rabies" for the tendency of the affected animal to be hyper-reactive to external stimuli and bite or attack anything near. In some cases, animals skip the excitative stage and develop paralysis, as in the third phase; the paralytic phase. This stage develops 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. == See also ==