Rabies

Rabies

Rabies (pronounced /ˈreɪbiːz/. From Latin: rabies) is a viral neuroinvasive 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 but occasionally by other forms of contact. Rabies is almost invariably fatal if post-exposure prophylaxis is not administered prior to the onset of severe symptoms. It is a significant killer of livestock in some countries.

The rabies virus travels to the brain by following the peripheral nerves. The incubation period of the disease depends on how far the virus must travel to reach the central nervous system, usually taking a few months.[1] Once the infection reaches the central nervous system and symptoms begin to show, the infection is practically untreatable and usually fatal within days.

Early-stage symptoms of rabies are malaise, headache and fever, later progressing to more serious ones, including acute pain, violent movements, uncontrolled excitement, depression and inability to swallow water. Finally, the patient may experience periods of mania and lethargy, followed by coma. The primary cause of death is usually respiratory insufficiency.[1]

Etymology

The term is derived from the Latin rabies, "madness".[2] This, in turn, may have come from 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.[3]

Virology

The rabies virus is the type species of the Lyssavirus genus, which encompasses other similar viruses. 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. These genes are nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and the viral RNA polymerase (L).[4]

From the point of entry, the virus travels 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.

Symptoms

The period between infection and the first flu-like symptoms is normally 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.[5] 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. The disease itself was also once commonly known as hydrophobia, from this characteristic symptom.

Death almost invariably results two to ten days after the first symptoms; the few humans who are known to have survived the disease[citation needed] were all left with severe brain damage, with one exception (see Milwaukee protocol, below). It is neurotropic in nature.

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.[6] It is also possible to make the diagnosis from saliva, urine and cerebrospinal fluid samples, but this is not as sensitive. Inclusion bodies called Negri bodies are 100% diagnostic for rabies infection, but found only in 20% of cases.

The differential diagnosis in a case of suspected human rabies may initially include any cause of encephalitis, particularly 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.[7] Similarly, 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.[8] 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 be possible for low-income settings according to research reported on the Science Development Network website in 2008. Accurate rabies diagnosis can be done at a tenth of the cost, according to researchers from the Farcha Veterinary and Livestock Research Laboratory and the Support International Health Centre in N'Djamena, Chad. The scientists evaluated a method using light microscopy, cheaper than the standard tests, and say this could provide better rabies control across Africa.[9]

Prevention

Almost every infected case with rabies resulted in death until a vaccine was developed by Louis Pasteur and Émile Roux in 1885. Their original vaccine was harvested from infected rabbits, from which the nerve tissue was weakened by allowing it to dry for five to ten days.[10] Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines.[11] The human diploid cell rabies vaccine (H.D.C.V.) was started in 1967; however, a new and less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available.[citation needed] A recombinant vaccine called V-RG has been successfully used in the field in Belgium, France, Germany and the United States to prevent outbreaks of rabies in wildlife.[12] 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.[citation needed]

In the U.S., 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 twentieth century, to 1–2 per year, mostly caused by bat bites, which may go unnoticed by the victim and hence untreated.[13]

Treatments

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, generally within ten days of infection. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is very effective at 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.”[14] In the United States, patients receive one dose of human rabies immunoglobulin (HRIG) and five doses of rabies vaccine over a twenty-eight day period. The immunoglobulin dose should not exceed 20 units per kilogram body weight. 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, fourteen, and twenty-eight after the first. Patients that have previously received pre-exposure vaccination do not receive the immunoglobulin, only the post-exposure vaccinations on day 0 and 3.

Modern cell-based vaccines are similar to flu shots in terms of pain and side effects. The old nerve-tissue-based vaccinations require multiple painful injections into the abdomen with a large needle, are cheap, and are now used only in remote poor areas in India, but are being phased out and replaced by affordable WHO ID (intradermal) vaccination regimes.

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.

Finding a bat in the room of a sleeping infant 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.[15]
Most official documentation on rabies on the internet and otherwise warn that treatment becomes futile with the onset of prodrome (when symptoms begin to appear). These texts are written to convince the layman not to delay seeking treatment (and rightly so).[citation needed] However, this may also lead them to falsely conclude that their situation is not an urgency and that treatment is possible up until the very end of the incubation period, as it may last 1 to 3 months on average; or it may at least convince them that it is safe to delay treatment by a few days. While the virus is treatable only during the incubation period, it is important to note that it is not treatable during its entirety. Rabies is fully treatable while the virus is present in tissues composed of cells other than neurons, such as skin and muscle. However, once the infection spreads to a neuron, the virus is sequestered from the immune system and will eventually make its way to the spinal cord and then to the brain. Treatment at this point may not be effective, even though symptoms may begin to appear weeks or even months later. Therefore, it is highly recommended that P.E.P. be administered as soon as possible. Begun without delay, or with very little delay, P.E.P. is 100% effective against rabies.[16] In the case in which there has been a significant delay in administering P.E.P., the treatment should be administered regardless of that delay, as it may still be effective if it is not too late.[citation needed] 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.[citation needed]

Rabies
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It is a significant killer of livestock in some countries. The rabies virus travels to the brain by following the peripheral nerves. The incubation period of the disease depends on how far the virus must travel to reach the central nervous system, usually taking a few months.[1] Once the infection reaches the central nervous system and symptoms begin to show, the infection is practically untreatable and usually fatal within days. Early-stage symptoms of rabies are malaise, headache and fever, later progressing to more serious ones, including acute pain, violent movements, uncontrolled excitement, depression and inability to swallow water. Finally, the patient may experience periods of mania and lethargy, followed by coma. The primary cause of death is usually respiratory insufficiency.[1] Etymology The term is derived from the Latin rabies, "madness".[2] This, in turn, may have come from 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.[3] Virology The rabies virus is the type species of the Lyssavirus genus, which encompasses other similar viruses. 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. These genes are nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and the viral RNA polymerase (L).[4] From the point of entry, the virus travels 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. Symptoms The period between infection and the first flu-like symptoms is normally 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.[5] 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. The disease itself was also once commonly known as hydrophobia, from this characteristic symptom. Death almost invariably results two to ten days after the first symptoms; the few humans who are known to have survived the disease[citation needed] were all left with severe brain damage, with one exception (see Milwaukee protocol, below). It is neurotropic in nature. 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.[6] It is also possible to make the diagnosis from saliva, urine and cerebrospinal fluid samples, but this is not as sensitive. Inclusion bodies called Negri bodies are 100% diagnostic for rabies infection, but found only in 20% of cases. The differential diagnosis in a case of suspected human rabies may initially include any cause of encephalitis, particularly 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.[7] Similarly, 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.[8] 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 be possible for low-income settings according to research reported on the Science Development Network website in 2008. Accurate rabies diagnosis can be done at a tenth of the cost, according to researchers from the Farcha Veterinary and Livestock Research Laboratory and the Support International Health Centre in N'Djamena, Chad. The scientists evaluated a method using light microscopy, cheaper than the standard tests, and say this could provide better rabies control across Africa.[9] Prevention Almost every infected case with rabies resulted in death until a vaccine was developed by Louis Pasteur and Émile Roux in 1885. Their original vaccine was harvested from infected rabbits, from which the nerve tissue was weakened by allowing it to dry for five to ten days.[10] Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines.[11] The human diploid cell rabies vaccine (H.D.C.V.) was started in 1967; however, a new and less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available.[citation needed] A recombinant vaccine called V-RG has been successfully used in the field in Belgium, France, Germany and the United States to prevent outbreaks of rabies in wildlife.[12] 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.[citation needed] In the U.S., 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 twentieth century, to 1–2 per year, mostly caused by bat bites, which may go unnoticed by the victim and hence untreated.[13] Treatments 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, generally within ten days of infection. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is very effective at 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.”[14] In the United States, patients receive one dose of human rabies immunoglobulin (HRIG) and five doses of rabies vaccine over a twenty-eight day period. The immunoglobulin dose should not exceed 20 units per kilogram body weight. 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, fourteen, and twenty-eight after the first. Patients that have previously received pre-exposure vaccination do not receive the immunoglobulin, only the post-exposure vaccinations on day 0 and 3. Modern cell-based vaccines are similar to flu shots in terms of pain and side effects. The old nerve-tissue-based vaccinations require multiple painful injections into the abdomen with a large needle, are cheap, and are now used only in remote poor areas in India, but are being phased out and replaced by affordable WHO ID (intradermal) vaccination regimes. 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. Finding a bat in the room of a sleeping infant 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.[15] Most official documentation on rabies on the internet and otherwise warn that treatment becomes futile with the onset of prodrome (when symptoms begin to appear). These texts are written to convince the layman not to delay seeking treatment (and rightly so).[citation needed] However, this may also lead them to falsely conclude that their situation is not an urgency and that treatment is possible up until the very end of the incubation period, as it may last 1 to 3 months on average; or it may at least convince them that it is safe to delay treatment by a few days. While the virus is treatable only during the incubation period, it is important to note that it is not treatable during its entirety. Rabies is fully treatable while the virus is present in tissues composed of cells other than neurons, such as skin and muscle. However, once the infection spreads to a neuron, the virus is sequestered from the immune system and will eventually make its way to the spinal cord and then to the brain. Treatment at this point may not be effective, even though symptoms may begin to appear weeks or even months later. Therefore, it is highly recommended that P.E.P. be administered as soon as possible. Begun without delay, or with very little delay, P.E.P. is 100% effective against rabies.[16] In the case in which there has been a significant delay in administering P.E.P., the treatment should be administered regardless of that delay, as it may still be effective if it is not too late.[citation needed] 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.[citation needed]
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