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Rabies

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Rabies is an infectious viral disease primarily affecting animals; can be transmitted to humans through an infected animal's bite; if untreated, can result in paralysis and death.

Rabid dog
Rabid dog

The Rabies Virus

Rabies virus belongs to the order Mononegavirales, viruses with a nonsegmented, negative-stranded RNA genomes. Within this group, viruses with a distinct “bullet” shape are classified in the Rhabdoviridae family, which includes at least three genera of animal viruses, Lyssavirus, Ephemerovirus, and Vesiculovirus. The genus Lyssavirus includes rabies virus, Lagos bat, Mokola virus, Duvenhage virus, European bat virus 1 & 2 and Australian bat virus.

Structure

Rhabdoviruses are approximately 180 nm long and 75 nm wide. Rabies is an RNA virus. The genome encodes 5 proteins designated as N, P, M, G, and L. The order and relative size of the genes in the genome are shown in the figure below. The arrangement of these proteins and the RNA genome determine the structure of the rabies virus.

Rabies negri bodies brain
Rabies negri bodies brain

Replication

The fusion of the rabies virus envelope to the host cell membrane (adsorption) initiates the infection process. The interaction of the G protein and specific cell surface receptors may be involved.

Transmission

Rabies virus is transmitted through direct contact (such as through broken skin or mucous membranes in the eyes, nose, or mouth) with saliva or brain/nervous system tissue from an infected animal.

Animal bites

People usually get rabies from the bite of a rabid animal. It is also possible, but rare, for people to get rabies from non-bite exposures, which can include scratches, abrasions, or open wounds that are exposed to saliva or other potentially infectious material from a rabid animal. Other types of contact, such as petting a rabid animal or contact with the blood, urine or feces of a rabid animal, are not associated with risk for infection and are not considered to be exposures of concern for rabies.

Rabies Virus 3D
Rabies Virus 3D medical animation still showing rabies virus with length of about 180nm

Other modes of transmission

Other modes of transmission—aside from bites and scratches—are uncommon. Inhalation of aerosolized rabies virus is one potential non-bite route of exposure, but except for laboratory workers, most people won’t encounter an aerosol of rabies virus. Rabies transmission through corneal and solid organ transplants have been recorded, but they are also very rare. There have only been two known solid organ donor with rabies in the United States since 2008. Many organ procurement organizations have added a screening question about rabies exposure to their procedures for evaluating the suitability of each donor.

Prevention on pets

There are several things you can do to protect your pet from rabies.

First, visit your veterinarian with your pet on a regular basis and keep rabies vaccinations up-to-date for all cats, ferrets, and dogs.

Second, maintain control of your pets by keeping cats and ferrets indoors and keeping dogs under direct supervision.

Third, spay or neuter your pets to help reduce the number of unwanted pets that may not be properly cared for or vaccinated regularly.

Finally, call animal control to remove all stray animals from your neighborhood since these animals may be unvaccinated or ill.

Rabies patient
Rabies patient

Prevention in people

Understanding your rabies risk and knowing what to do after contact with animals can save lives. Any mammal can get rabies, but the most commonly affected animals in the United States are raccoons, skunks, bats, and foxes — so the best way to avoid rabies in the U.S. is to stay away from wildlife. Leave all wildlife alone, including injured animals. If you find an injured animal, don’t touch it; contact local authorities for assistance.

Rabies in dogs is still common in many countries outside the United States, so find out if rabies is present in dogs or wildlife at your destination before international travel.

Because pets can get rabies from wildlife and then could spread it to humans, preventing rabies in pets is also an important step in preventing human rabies cases.

If you do come into contact with a rabid animal, rabies in humans is 100% preventable through prompt appropriate medical care. If you are bitten, scratched, or unsure, talk to a healthcare provider about whether you need PEP.

Postexposure prophylaxis

Postexposure prophylaxis (PEP) consists of a dose of human rabies immune globulin (HRIG) and rabies vaccine given on the day of the rabies exposure, and then a dose of vaccine given again on days 3, 7, and 14. For people who have never been vaccinated against rabies previously, postexposure prophylaxis (PEP) should always include administration of both HRIG and rabies vaccine. The combination of HRIG and vaccine is recommended for both bite and non-bite exposures, regardless of the interval between exposure and initiation of treatment. People who have been previously vaccinated or are receiving preexposure vaccination for rabies should receive only vaccine.

Human rabies immune globulin

Human rabies immune globulin (HRIG) is administered only once, at the beginning of anti-rabies prophylaxis, to previously unvaccinated persons. This will provide immediate antibodies until the body can respond to the vaccine by actively producing antibodies of its own. If possible, the full dose of HRIG should be thoroughly infiltrated in the area around and into the wounds. Any remaining volume should be injected intramuscularly at a site distant from vaccine administration.

Rabies vaccine

A regimen of four 1-mL doses of HDCV or PCEC vaccines should be administered intramuscularly to previously unvaccinated persons.

The first dose of the four-dose course should be administered as soon as possible after exposure. Additional doses should be administered on days 3, 7, and 14 after the first vaccination. For adults, the vaccination should always be administered intramuscularly in the deltoid area (arm). For children, the anterolateral aspect of the thigh is also acceptable. The gluteal area should never be used for rabies vaccine injections because observations suggest administration in this area results in lower neutralizing antibody titers.

Vaccination

People who work with rabies in laboratory settings and animal control and wildlife officers are just a few of the people who should consider rabies preexposure vaccinations.

Child receiving rabies innoculation
Child receiving rabies innoculation

If you are traveling to a country where rabies is widespread, you should consult your doctor about the possibility of receiving preexposure vaccination against rabies.

Consider preexposure vaccination if:

Your planned activity will bring you into contact with wild or domestic animals, for example if you are a biologist, veterinarian, or agriculture specialist working with animals.

You will be visiting remote areas where medical care is difficult to obtain or may be delayed, for example, hiking through remote villages where dogs are common.

Your stay is longer than 1 month in an area where dog rabies is common. The longer your stay, the greater the chance of an encounter with an animal.

Although preexposure vaccination does not eliminate the need for additional therapy after a rabies exposure, it simplifies management by eliminating the need for rabies immune globulin and decreasing the number of doses of vaccine needed. This is of particular importance for persons at high risk for exposure to rabies in areas where immunizing products might not be available or where lesser quality biologics might be used which would place the exposed person at increased risk for adverse events.

Preexposure prophylaxis may also protect people whose postexposure therapy is delayed and provide protection to people who are at risk for unapparent exposures to rabies.

The distribution of the global burden of rabies
The distribution of the global burden of rabies

Signs and symptoms

After a bite or other rabies exposure, the rabies virus has to travel through the body to the brain before it can cause symptoms. This time between the exposure and the appearance of symptoms is called the incubation period, and it may last for weeks to months. The incubation period may vary based on the location of the exposure site (how far away it is from the brain), the type of rabies virus, and any existing immunity.

The first symptoms of rabies may be very similar to those of the flu including general weakness or discomfort, fever, or headache. These symptoms may last for days.

There may be also discomfort or a prickling or itching sensation at the site of the bite, progressing within days to acute symptoms of cerebral dysfunction, anxiety, confusion, and agitation. As the disease progresses, the person may experience delirium, abnormal behavior, hallucinations, hydrophobia (fear of water), and insomnia. The acute period of disease typically ends after 2 to 10 days. Once clinical signs of rabies appear, the disease is nearly always fatal, and treatment is typically supportive. To date less than 20 cases of human survival from clinical rabies have been documented, and only a few survivors had no history of pre- or postexposure prophylaxis.

The signs, symptoms, and outcome of rabies in animals can vary, but are often similar to those in humans, including early nonspecific symptoms, acute neurologic symptoms, and ultimately death.

Diagnosis

In animals, rabies is diagnosed using the direct fluorescent antibody (DFA) test, which looks for the presence of rabies virus antigens in brain tissue. In humans, several tests are required.

Rapid and accurate laboratory diagnosis of rabies in humans and other animals is essential for timely administration of postexposure prophylaxis. Within a few hours, a diagnostic laboratory can determine whether or not an animal is rabid and inform the responsible medical personnel. The laboratory results may save a patient from unnecessary physical and psychological trauma, and financial burdens, if the animal is not rabid.

In addition, laboratory identification of positive rabies cases may aid in defining current epidemiologic patterns of disease and provide appropriate information for the development of rabies control programs.

The nature of rabies disease dictates that laboratory tests be standardized, rapid, sensitive, specific, economical, and reliable.

Rabies should be considered in patients with signs or symptoms of encephalitis or myelitis, including autonomic instability, dysphagia, hydrophobia, paresis, and paresthesia, particularly if a nonspecific prodrome preceded the onset of these signs by three to four days. Progressive worsening of neurologic signs is characteristic of rabies and should be considered as a positive indicator for rabies.

Laboratory tests to rule out common encephalitides (herpes, enteroviruses, arboviruses) should be performed. Negative results of these tests would increase the likelihood of rabies as the diagnosis. If a patient presents with symptoms similar to the ones described above, but the neurologic status does not change and the illness continues for longer than three weeks, rabies is unlikely as the diagnosis.

Positive Indicators for Rabies

Nonspecific prodrome prior to onset of neurologic signs Neurologic signs consistent with encephalitis or myelitis dysphagia hydrophobia paresis Progression of neurologic signs Negative test results for other etiologies of encephalitis

Negative Indicators for Rabies

Improvement or no change in neurologic status Illness with ” 2 to 3 week duration


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