Rabies overview

# Overview
Rabies is a viral zoonotic disease that causes acute encephalitis (inflammation of the brain) in mammals. In non-vaccinated humans, rabies is almost invariably fatal after neurological symptoms have developed, but prompt post-exposure vaccination may prevent the virus from progressing. The rabies virus is categorized as a Lyssavirus. The molecular biology of rabies consists of bullet shaped virus with helical symmetry that has a length of approximately 180 nm. Rabies typically has its greatest effect on the brain. Rabies is typically defined by encephalitis and myelitis. Various carnivorous animal species have been identified as the source of rabies virus (RV). In Africa and Asia, domestic dogs are the main reservoirs of rabies virus infection. Whereas, in the United States, racoons, foxes, skunks, coyotes, possums and bats are understood to be responsible for the spread of rabies virus. RV infects neurons and leads to the degeneration of the neuronal processes by disrupting cytoskeletal integrity. The differential diagnosis for rabies deals with eliminating diseases with similar symptoms from the diagnosis. There are many viruses that can appear similar to rabies such as encephalitis and the herpes simplex virus. According to the World Health Organization (WHO), human rabies is present in 150 countries and territories and on all continents, except for Antarctica. India has been known to have the highest incidence of rabies. A bite from an infected animal is the biggest risk factor. Rabies is a clinical diagnosis that includes a thorough medical history and a high degree of suspicion. Patients are asymptomatic during the incubation period. Prodromal symptoms may include low-grade fever, chills, malaise, myalgias, weakness, fatigue, anorexia, sore throat, nausea, vomiting and headache. Clinical rabies can present as encephalitic ("furious") rabies or paralytic ("dumb") rabies. Rabies eventually results in progressive encephalopathy, respiratory arrest, coma and death within 10 days of the onset of symptoms. Common physical examination findings of rabies include hyperpyrexia alternating with hypothermia, tachycardia, respiratory collapse, hypersalivation, lacrimation, sweating, dilatation of the pupils and bradycardia. Skin findings may include percussion myoedema, bite marks and bruises. Lumbar puncture may show lymphocytic pleocytosis, CSF protein-elevation and normal glucose concentration. Patients with suspected exposure to rabies or asymptomatic patients can benefit from thorough wound cleaning followed by a combined rabies vaccination and immune globulin administration, these patients have a good prognosis. Human diploid cell rabies vaccines are made using the attenuated Pitman-Moore L503 strain of the virus. Human diploid cell rabies vaccines have been given to more than 1.5 million humans as of 2006. Treatment after exposure, known as post-exposure prophylaxis or "P.E.P.", is highly successful in preventing the disease if administered promptly, within fourteen days after infection. The first step is immediately washing the wound with soap and water, which is very effective at reducing the number of viral particles. In the United States, patients receive one dose of immunoglobulin and five doses of rabies vaccine over a twenty-eight day period. One-half the dose of immunoglobulin is injected in the region of the bite, if possible, with the remainder injected intramuscularly away from the bite.

# Historical Perspective
Rabies is a disease that has been classically associated with infected animals, mainly dogs.The first written record of rabies is in the Codex of Eshnunna (ca. 1930 BC - written prior to the Code of Hammurabi), which demonstrates that the owner of a dog showing symptoms of rabies should take preventive measure against bites. Although dogs are viewed as the main culprit of rabies, rabies is also associated with animals such as possums, skunks, and more importantly, bats. In 1885, 9-year-old boy named Joseph Meister was the first person to have received an effective shot for rabies after being bitten by a rabid dog. Louis Pasteur treated the first case of rabies by a weak form of virus (which later became the basis of active immunization for rabies). In the 1950s, people who had been bitten by a rabid animal got 23 shots along the abdomen. Today, the shots are more effective and less painful. They consist of a series of 6 shots given in the arm over a 1 month period. One shot is given around the bite and the rest are given in the arm.

# Pathophysiology
The rabies virus is categorized as a Lyssavirus. The molecular biology of rabies consists of bullet shaped virus with helical symmetry that has a length of approximately 180 nm. Rabies typically has its greatest effect on the brain. Rabies is typically defined by encephalitis and myelitis. Various carnivorous animal species have been identified as the source of rabies virus (RV). In Africa and Asia, domestic dogs are the main reservoirs of rabies virus infection. Whereas, in the United States, racoons, foxes, skunks, coyotes, possums and bats are understood to be responsible for the spread of rabies virus.The neuromuscular junction is the major site of entry into neurons. RV infects peripheral nervesand then reaches the central nervous system (CNS) via retrograde axonal transport. The primary mechanism involved in the neuroinvasion of RV is trans-synaptic neuronalspread. RV infects neurons and leads to the degeneration of the neuronal processes by disrupting cytoskeletal integrity. Histopathologic evidence of rabies encephalomyelitis(inflammation) in brain tissue and meninges includes, mononuclear infiltration, perivascular cuffing of lymphocytes or polymorphonuclear cells, lymphocytic foci, Babes nodules consisting of glial cells and Negri bodies.

# Causes
The Rabies virus is the cause of rabies.

# Differentiating Rabies from other Diseases
The differential diagnosis for rabies deals with eliminating diseases with similar symptoms from the diagnosis. There are many viruses that can appear similar to rabies such as encephalitis and the herpes simplex virus. It is very important to rule out certain diseases such as echovirus and poliovirus. Rabies is a serious disease that needs to be treated quickly if someone is suspected to be infected with the virus.

# Epidemiology and Demographics
According to the World Health Organization (WHO), human rabies is present in 150 countries and territories and on all continents, except for Antarctica. India has been known to have the highest incidence of rabies. Twenty-three cases of human rabies have been reported in the United States in the past decade (2008-2017). Many territories, such as the United Kingdom, Ireland, Taiwan, Japan, Hawaii, Mauritius, Barbados and Guam, are free of rabies. Worldwide, 55,000 human deaths occur annually from rabies, with 56 % of deaths estimated to occur in Asia and 44 % in Africa.

# Risk Factors
A bite from an infected animal is the biggest risk factor. People that live in an area, or travel to an area that has a large incidence for rabies, are at a high risk for acquiring rabies from a rabid animal. Handling certain wild animals such as bats or raccoons will put a person at a higher risk.

# Screening
There is insufficient evidence to recommend routine screening for rabies. Enzyme immunoassay (EIA) is currently under investigation as a convenient test for screening hybridoma supernatants because nanogram amounts of antibody can be detected and up to 100 samples can be tested at the same time.

# Natural history, complications and prognosis
If left untreated, rabies runs its course very rapidly. Once symptoms begin to appear, the disease is almost always fatal. The acute period of disease typically ends after 2 to 10 days. Common complications of rabies include, psychosis, seizures, aphasia, muscular twitching, delirium and death. Treatment after exposure (receiving the vaccines), known as post-exposure prophylaxis (PEP), is highly successful in preventing the disease if administered promptly, in general within ten days of infection.

# Diagnosis

## Diagnostic criteria
Rabies is a clinical diagnosis that includes a thorough medical history and a high degree of suspicion. Laboratory findings that help with the diagnosis of rabies include skin biopsy specimens showing virus-specific immunofluorescent staining, isolation of virus from the samples of saliva and detection of anti-rabies antibodies in serum or cerebrospinal fluid (CSF).

## History and symptoms
The symptoms of rabies depend upon the stage of the disease at the time of presentation. Rabies may present during incubation period, prodromal period, acute neurologic period (clinical rabies), or coma. Patients are asymptomatic during the incubation period. Prodromal symptoms may include low-grade fever, chills, malaise, myalgias, weakness, fatigue, anorexia, sore throat, nausea, vomiting and headache. Clinical rabies can present as encephalitic ("furious") rabies or paralytic ("dumb") rabies. Encephalitic rabies is more common and presents as hydrophobia, aerophobia, facial grimace, opisthotonos, autonomic instability, dysarthria, dysphagia, and diplopia. Rabies eventually results in progressive encephalopathy, respiratory arrest, coma and death within 10 days of the onset of symptoms.

## Physical examination
Common physical examination findings of rabies include hyperpyrexia alternating with hypothermia, tachycardia, respiratory collapse, hypersalivation, lacrimation, sweating, dilatation of the pupils and bradycardia. Skin findings may include percussion myoedema, bite marks and bruises.

## Laboratory findings
Routine lab findings are non-specific and may include peripheral leukocytosis, respiratory alkalosis followed by respiratory acidosis, albuminuria and pyuria. Lumbar puncturemay show lymphocytic pleocytosis, CSF protein-elevation and normal glucose concentration. Serology is useful in assessing the serostatus in immunized humans and animals as it is difficult to document the neutralizing antibody response via immunofluorescence because mostly death occurs prior to mounting a response. Serologic tests include reverse transcriptase polymerase chain reaction (RT-PCR), viral culture, immunofluorescence staining, indirect immunofluorescence, direct fluorescent antibody test (dFA) and virus neutralization assays.

## Electrocardiogram
EKG findings may show supraventricular arrhythmias, atrioventricular block, sinus bradycardia, sinus arrest with non-specific ST segment and T-wave changes.

## Chest X-ray
CXR may show infiltrates secondary to aspiration, pneumonia, acute respiratory distress syndrome and congestive heart failure.

## CT
CT is usually normal. Late findings may include cerebral edema and decreased attenuation in the hippocampus, brain stem, basal ganglia, and periventricular white matter.

## MRI
Findings on MRI suggestive of rabies include areas of increased T2 intensity (flare) may be seen in hippocampus, hypothalamus, and brainstem.

# Treatment

## Medical therapy
Two presentations must be considered in the treatment of rabies. Symptomatic patients with delayed presentation in the emergency department, associated with a low survival rate and treated with "Milwaukee protocol" (which is still being studied) and patients with a suspected exposure to rabies virus or early diagnosed asymptomatic rabies patients. Patients with suspected exposure to rabies or asymptomatic patients can benefit from thorough wound cleaning followed by a combined rabies vaccination and immune globulin administration, these patients have a good prognosis.

## Surgery
Immediate gentle irrigation with water or a dilute water povidone-iodine solution has been shown to markedly decrease the risk of bacterial infection. Wound cleansing is especially important in rabies prevention.

## Primary prevention
There is no known cure for symptomatic rabies, but it can be prevented by vaccination, both in humans and other animals. Virtually every infection with rabies was a death sentence, until Louis Pasteur and Emile Roux developed the first rabies vaccination in 1885. This vaccine was first used on a human on July 6, 1885  nine-year old boy Joseph Meister (18761940) had been mauled by a rabid dog.Their vaccine consisted of a sample of the virus harvested from infected (and necessarily dead) rabbits, which was weakened by allowing it to dry. Similar nerve tissue-derived vaccines are still used now in some countries, and while they are much cheaper than modern cell culture vaccines, they are not as effective and carry a certain risk of neurological complications.The human diploid cell rabies vaccine (H.D.C.V.) was started in 1967. Human diploid cell rabies vaccines are made using the attenuated Pitman-Moore L503 strain of the virus. Human diploid cell rabies vaccines have been given to more than 1.5 million humans as of 2006. Newer and less expensive purified chicken embryo cell vaccine, and purified Vero cell rabies vaccine are now available. The purified Vero cell rabies vaccine uses the attenuated Wistar strain of the rabies virus, and uses the Vero cell line as its host.

## Secondary prevention
Treatment after exposure, known as post-exposure prophylaxis or "P.E.P.", is highly successful in preventing the disease if administered promptly, within fourteen days after infection. The first step is immediately washing the wound with soap and water, which is very effective at reducing the number of viral particles. In the United States, patients receive one dose of immunoglobulin and five doses of rabies vaccine over a twenty-eight day period. One-half the dose of immunoglobulin is injected in the region of the bite, if possible, with the remainder injected intramuscularly away from the bite. Pre-exposure vaccination with human diploid cell Rabies vaccine (HDCV), or purified chick embryo cell (PCEC) vaccine, may be recommended for international travelers based on the local incidence of rabies in the country to be visited, the availability of appropriate antirabies biologicals, and the intended activity and duration of stay of the traveler.