Contents1. Introduction2. Signs and symptoms3. Virology4. Diagnosis5. Prevention6. Management6.1 Post-exposure prophylaxis6.2 Blood-brain barrier6.3 Induced coma
7. Prognosis8. Epidemiology8.1 Transmission8.2 Prevalence9. History9.1 Etymology9.2 Impact10 In other animals11 Research and gene therapy uses
Rabies ( From Latin: rabies, "madness") is a viral diseasethat causes acute encephalitis (inflammation of the brain) inwarm-blooded animals. It is zoonotic (i.e., transmitted byanimals), 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 onsetof severe symptoms. The rabies virus infects the centralnervous system, ultimately causing disease in the brain anddeath.The rabies virus travels to the brain by following theperipheral nerves. The incubation period of the disease isusually a few months in humans, depending on the distancethe virus must travel to reach the central nervous system.Once the rabies virus reaches the central nervous systemand symptoms begin to show, the infection is effectivelyuntreatable and usually fatal within days.
Early-stage symptoms of rabies are malaise, headache andfever, progressing to acute pain, violent movements,uncontrolled excitement, depression, andhydrophobia.Finally, the patient may experience periods ofmania and lethargy, eventually leading to coma. Theprimary cause of death is usually respiratory insufficiency.Worldwide, roughly 97% of rabies cases come from dogbites. In the United States, however, animal control andvaccination programs have effectively eliminated domesticdogs as reservoirs of rabies.In several countries, includingAustralia, Japan, and the United Kingdom, rabies carried byanimals that live on the ground has been eradicatedentirely.
Signs and symptomsThe period between infection and the first flu-likesymptoms is normally two to twelve weeks, but canbe as long as two years. Soon after, the symptomsexpand to slight or partial paralysis, cerebraldysfunction, anxiety, insomnia, confusion,agitation, abnormal behavior, paranoia, terror,hallucinations, progressing to delirium.Theproduction of large quantities of saliva and tearscoupled with an inability to speak or swallow aretypical during the later stages of the disease; thiscan result in hydrophobia, in which the patient hasdifficulty swallowing because the throat and jawbecome slowly paralyzed, shows panic when
Death almost invariably results two to tendays after first symptoms. In 2005, the firstpatient was treated with the Milwaukeeprotocol, and Jeanna Giese became the firstperson ever recorded to survive rabieswithout receiving successful post-exposureprophylaxis. An intention to treat analysishas since found that this protocol has asurvival rate of about 8%.
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. Thegenetic information is packaged as aribonucleoprotein complex in which RNA is tightlybound by the viral nucleoprotein. The RNA genomeof the virus encodes five genes whose order ishighly conserved: nucleoprotein (N),phosphoprotein (P), matrix protein (M),glycoprotein (G), and the viral RNA polymerase (L).Once inside a muscle or nerve cell, the virusundergoes replication. The trimeric spikes on theoutside of the membrane of the virus interact witha specific cell receptor, the most likely one beingthe acetylcholine receptor. The cell membranepinches in a process known as pinocytosis andallows entry of the virus into the cell by way of an
The virus then utilizes the acidic environment ofthat endosome and binds to its membranesimultaneously releasing its five proteins andsingle strand RNA into the cytoplasm. The L proteinthen transcribes 5 mRNA strands and a positivestrand of RNA all from the original negative strandRNA using free nucleotides in the cytoplasm. These5 mRNA strands are then translated into theircorresponding proteins (P,L,N,G,M proteins) at freeribosomes in the cytoplasm. Some proteins requirepost-translational modifications. For example, theG protein travels through the rough endoplasmicreticulum where it undergoes further folding, andis then transported to the Golgi Apparatus where asugar group is added to it (glycosylation).
Where there are enough proteins, the viralpolymerase will begin to synthesize new negativestrands of RNA from the template of the positivestrand RNA. These negative strands will then formcomplexes with the N,P,L, and M proteins and thentravel to the inner membrane of the cell were a Gprotein has embedded itself in the membrane. TheG protein then coils around the N-P-L-M complexof proteins taking some of the host cell membranewith it which will form the new outer envelope ofthe virus particle. The virus then buds from cell.From the point of entry, the virus isneurotropic, traveling quickly along the neuralpathways into the central nervous system(CNS), and then further into other organs.Thesalivary glands receive high concentrations of the
DiagnosisThe reference method for diagnosing rabies is byperforming PCR or viral culture on brain samplestaken after death. The diagnosis can also bereliably made from skin samples taken beforedeath.It is also possible to make the diagnosis fromsaliva, urine and cerebrospinal fluid samples, butthis is not as sensitive. Cerebral inclusion bodiescalled Negri bodies are 100% diagnostic for rabiesinfection, but are found in only about 80% of cases.If possible, the animal from which the bite wasreceived should also be examined for rabies.
The differential diagnosis in a case of suspectedhuman rabies may initially include any cause ofencephalitis, in particular infection with virusessuch as herpesviruses, enteroviruses, andarboviruses (e.g., West Nile virus). The mostimportant viruses to rule out are herpes simplexvirus type 1, varicella-zoster virus, and (lesscommonly) enteroviruses, includingcoxsackieviruses, echoviruses, polioviruses, andhuman enteroviruses 68 to 71.New causes of viral encephalitis are alsopossible, as was evidenced by the recent outbreakin Malaysia of some 300 cases of encephalitis(mortality rate, 40%) caused by Nipah virus, a newlyrecognized paramyxovirus.
Likewise, well-known viruses may be introducedinto new locations, as is illustrated by the recentoutbreak of encephalitis due to West Nile virus inthe eastern United States.Epidemiologic factors(e.g., season, geographic location, and the patientsage, travel history, and possible exposure toanimal bites, rodents, and ticks) may help directthe diagnostic workup.Cheaper rabies diagnosis will become possible forlow-income settings: accurate rabies diagnosis canbe done at a tenth of the cost of traditional testingusing 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 usedin some countries, as they are much cheaper thanmodern cell culture vaccines. The human diploidcell rabies vaccine was started in 1967; however, anew and less expensive purified chicken embryocell vaccine and purified vero cell rabies vaccine arenow available.A recombinant vaccine called V-RGhas been successfully used inBelgium, France, Germany, and the United States toprevent outbreaks of rabies in wildlife.Currentlypre-exposure immunization has been used in bothhuman and non-human populations, whereas inmany jurisdictions domesticated animals arerequired to be vaccinated.
In the USA, since the widespread vaccinationof domestic dogs and cats and thedevelopment of effective human vaccinesand immunoglobulin treatments, the numberof recorded deaths from rabies has droppedfrom one hundred or more annually in theearly 20th century, to 1–2 per year, mostlycaused by bat bites, which may go unnoticedby the victim and hence untreated.
The Missouri Dept. of Health and Senior ServicesCommunicable Disease Surveillance 2007 Annual Reportstates that the following can help reduce the risk ofexposure 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 wildanimal or a stray,especially if the animal is acting strangely. * Washing the wound with soap and water between 10 to15 minutes, if you do get bitten by an animal, andcontacting your healthcare provider to see whether youneed rabies post-exposure prophylaxis. * Getting pets spayed or neutered. Pets that are sterile areless likely to leave home, become strays, and reproducemore stray animals.
September 28 is World Rabies Day, which promotesinformation on, and prevention and elimination ofthe disease.
ManagementPost-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 ormouth should be flushed well with water."In the United States, the Centers for DiseaseControl and Prevention (CDC) recommend patientsreceive one dose of human rabies immunoglobulin(HRIG) and four doses of rabies vaccine over afourteen-day period. The immunoglobulin doseshould not exceed 20 units per kilogram bodyweight. HRIG is very expensive and constitutes thevast majority of the cost of post-exposuretreatment, ranging as high as several thousanddollars. As much as possible of this dose should beinfiltrated around the bites, with the remainderbeing given by deep intramuscular injection at asite distant from the vaccination site.
The first dose of rabies vaccine is given as soon aspossible after exposure, with additional doses ondays three, seven and fourteen after the first.Patients who have previously received pre-exposure vaccination do not receive theimmunoglobulin, only the post-exposurevaccinations on day 0 and 2.Modern cell-based vaccines are similar to flu shotsin terms of pain and side-effects. The old nerve-tissue-based vaccinations that require multiplepainful injections into the abdomen with a largeneedle are cheap, but are being phased out andreplaced by affordable WHO ID (intradermal)vaccination regimens.Intramuscular vaccinationshould be given into the deltoid, not gluteal area,which has been associated with vaccination failure
Awakening to find a bat in the room, or finding abat in the room of a previously unattended child ormentally disabled or intoxicated person, isregarded as an indication for post-exposureprophylaxis. The recommendation for theprecautionary use of post-exposure prophylaxis inoccult bat encounters where there is no recognizedcontact has been questioned in the medicalliterature, based on a cost-benefit analysis.However, recent studies have further confirmed thewisdom of maintaining the current protocol ofprecautionary administering of PEP in cases wherea child or mentally compromised individual hasbeen left alone with a bat, especially in sleepareas, where a bite or exposure may occur whilethe victim is asleep and unaware or awake and
This is illustrated by the September 2000 case of a nine-year-old boy from Quebec who died from rabies threeweeks after being in the presence of a sick bat, even thoughthere was no apparent report of a bite, as shown in thefollowing conclusion made by the doctors involved in thecase:Despite recent criticism , the dramatic circumstancessurrounding our patients history, as well as increasinglyfrequent reports of human rabies contracted in NorthAmerica, support the current Canadian guidelines that statethat RPEP [PEP] is appropriate in cases where a significantcontact with a bat cannot be excluded . The notion that abite or an overt break in the skin needs to be seen or feltfor rabies to be transmitted by a bat is a myth in manycases.It is highly recommended that PEP be administered assoon as possible. Begun with little or no delay, PEP is 100%effective against rabies.In the case in which there has beena significant delay in administering PEP, the treatmentshould be administered regardless of that delay, as it may
Blood-brain barrierDuring lethal rabies infection of mice, the blood-brain barrier (BBB) does not allow anti-viralimmune cells to enter the brain, the primary site ofrabies virus replication.This aspect contributes tothe pathogenicity of the virus and artificiallyincreasing BBB permeability promotes viralclearance.
Induced comaIn 2004, American teenager Jeanna Giese survivedan infection of rabies unvaccinated. She was placedinto an induced coma upon onset of symptoms andgiven ketamine, midazolam, ribavirin, andamantadine. Her doctors administered treatmentbased on the hypothesis that detrimental effects ofrabies were caused by temporary dysfunctions inthe brain and could be avoided by inducing atemporary partial halt in brain function that wouldprotect the brain from damage while giving theimmune system time to defeat the virus. Afterthirty-one days of isolation and seventy-six days ofhospitalization, Giese was released from thehospital. She survived with almost no permanentafter-effects and as of 2009 was starting her third
Gieses treatment regimen became known as the "Milwaukeeprotocol", which has since undergone revision (the secondversion omits the use of ribavirin). There were two survivorsout of 25 patients treated under the first protocol. A further10 patients have been treated under the revised protocoland there have been a further two survivors. The anestheticdrug ketamine has shown the potential for rabies virusinhibition in rats and is used as part of the Milwaukeeprotocol.On April 10, 2008 in Cali, Colombia, an eleven-year-oldboy was reported to survive rabies and the induced comawithout noticeable brain damage.On June 12, 2011, Precious Reynolds, an eight-year-old girlfrom Humboldt County, California, became the thirdreported person in the United States to have recovered fromrabies without receiving post-exposure prophylaxis
PrognosisTreatment after exposure (receiving the vaccines),known as post-exposure prophylaxis (PEP), ishighly successful in preventing the disease ifadministered promptly, in general within ten daysof infection. Begun with little or no delay, PEP is100% effective against rabies. In the case in whichthere has been a significant delay in administeringPEP, the treatment should be administeredregardless of that delay, as it may still be effective.In unvaccinated humans, rabies is usually fatalafter neurological symptoms have developed, butprompt post-exposure vaccination may prevent thevirus from progressing. Rabies kills around 55,000people a year, mostly in Asia and Africa.
EpidemiologyTransmissionAny warm-blooded animal (including humans) maybecome infected with the rabies virus and developsymptoms (although birds have only been knownto be experimentally infected. Indeed the virus haseven been adapted to grow in cells ofpoikilothermic ("cold-blooded") vertebrates.Most animals can be infected by the virus and cantransmit the disease to humans.
Most animals can be infected by the virus and cantransmit the disease to humans. Infectedbats, monkeys, raccoons, foxes, skunks, cattle, wolves, coyotes, dogs, mongoose (normally yellowmongoose)or cats present the greatest risk tohumans. Rabies may also spread through exposureto infected domestic farmanimals, groundhogs, weasels, bears and otherwild carnivores. Small rodents such assquirrels, hamsters, guineapigs, gerbils, chipmunks, The virus is usuallypresent in the nerves and saliva of a symptomaticrabid animal. rats, and mice and lagomorphs likerabbits and hares are almost never found to beinfected with rabies and are not known to transmitrabies to humans.The Virginia opossum is resistant
The route of infection is usually, but not always, bya bite. In many cases the infected animal isexceptionally aggressive, may attack withoutprovocation, and exhibits otherwise-uncharacteristic behavior.Transmission betweenhumans is extremely rare. A few cases have beenrecorded through transplant surgery.After a typicalhuman infection by bite, the virus enters theperipheral nervous system. It then travels along thenerves toward the central nervous system. Duringthis phase, the virus cannot be easily detectedwithin the host, and vaccination may still confercell-mediated immunity to prevent symptomaticrabies. When the virus reaches the brain, it rapidlycauses encephalitis. This is called the prodromalphase, and is the beginning of the symptoms. Once
PrevalenceThe rabies virus survives in widespread, varied,rural fauna reservoirs. It is present in the animalpopulations of almost every country in the world,except in Australia and New Zealand. Australian BatLyssavirus (ABLV) discovered in 1996 is similar torabies, and is believed to be prevalent in native batpopulations. In some countries, like those inwestern Europe and Oceania, rabies is consideredto be prevalent among bat populations only.In Asia, parts of the Americas, and large parts ofAfrica, dogs remain the principal host.
Mandatory vaccination of animals is less effectivein rural areas. Especially in developingcountries, pets may not be privately kept and theirdestruction may be unacceptable. Oral vaccines canbe safely distributed in baits, a practice that hassuccessfully reduced rabies in rural areas ofCanada, France, and the USA. InMontréal, Canada, baits are successfully used onraccoons in the Mont-Royal Park area. Vaccinationcampaigns may be expensive, and cost-benefitanalysis suggests that baits may be a cost effectivemethod of control.
There are an estimated 55,000 human deathsannually from rabies worldwide, with about 31,000in Asia, and 24,000 in Africa. One of the sources ofrecent flourishing of rabies in East Asia is the petboom. China introduced the "one-dog policy" inthe city of Beijing in November 2006 to control theproblem. India has been reported as having thehighest rate of human rabies in the world, primarilybecause of stray dogs.As of 2007, Vietnam had thesecond-highest rate, followed by Thailand; in thesecountries the virus is primarily transmitted throughcanines (feral dogs and other wild canine species).
Rabies is common among wild animals in theUnited States. Bats, raccoons, skunks and foxesaccount for almost all reported cases (98% in2009). Rabid bats are found in all 48 contiguousstates. Other reservoirs are more limitedgeographically: for example, the raccoon rabiesvirus variant is only found in a relatively narrowband along the East Coast. Due to a high publicawareness of the virus, efforts at vaccination ofdomestic animals and curtailment of feralpopulations, and availability of post-exposureprophylaxis, incidents of rabies in humans are veryrare. There was a total of 45 cases of the disease inthe country in 1995-2010; of these, 9 are thoughtto have been acquired abroad. Almost alldomestically acquired cases are attributed to bat
HistoryEtymologyThe term is derived fromthe Latin rabies, "madness". This, in turn, may berelated to the Sanskrit rabhas, "to do violence". TheGreeks derived the word "lyssa", from "lud" or"violent"; this root is used in the name of the genusof rabies lyssavirus.
ImpactBecause of its potentially violent nature, rabies hasbeen known since c.2000 B.C. The first writtenrecord of rabies is in the Mesopotamian Codex ofEshnunna (ca. 1930 BC), which dictates that theowner of a dog showing symptoms of rabiesshould take preventive measure against bites. Ifanother person was bitten by a rabid dog and laterdied, the owner was heavily fined.Rabies was considered a scourge for its prevalencein the 19th century. In France and Belgium, whereSaint Hubert was venerated, the "St Huberts Key"was heated and applied to cauterize the wound; byan application of magical thinking, dogs werebranded with the key in hopes of protecting themfrom rabies.
Fear of rabies related to methods of transmissionswas almost irrational;however, this gave LouisPasteur ample opportunity to test post-exposuretreatments from 1885. In ancient medicaltimes, the attachment of the tongue (the frenumlinguae, a mucous membrane) was cut andremoved from where they thought the rabies camefrom. This changed once they found the actualcause of rabies.
In other animals stages ofRabies is infectious to mammals. Threerabies are recognized in dogs and other animals.The first stage is a one- to three-day periodcharacterized by behavioral changes and is knownas theprodromal stage. The second stage is theexcitative stage, which lasts three to four days. It isthis stage that is often known as furious rabies forthe tendency of the affected animal to behyperreactive to external stimuli and bite atanything near. The third stage is the paralytic stageand is caused by damage to motor neurons.Incoordination is seen owing to rearlimb paralysis and drooling and difficultyswallowing is caused by paralysis of facial and
Research and genetherapy usesRabies has the advantage overother pseudotyping methods for gene delivery inthat the cell targeting (tissue tropism) is morespecific for difficult to reach sites such asthe central nervous systemwithout invasive deliverymethods as well as capable of retrograde tracing(i.e. going against the flow of informationat synapses) in neuronal circuits.