Rage

Rabies is an acute, infectious, zoonotic viral disease. It is caused by a Rhabdoviridae that attacks the central nervous system, causing encephalitis with a lethality close to 100%.

The rabies virus belongs to the Rhabdoviridae family, genus Lyssavirus type 1, is bullet- or rod-shaped, and measures between 130 and 240 by 65 to 80 nm. This virus consists of a single strand of RNA. Its envelope is made up of a layer of lipids whose surface contains five structural proteins: G (glycoprotein) that alternates with M1 and M2 proteins (matrix proteins); in the nucleocapsid are the proteins N (nucleoprotein), NS (nucleocapsid) and L (transcriptase). The glycoprotein is the major antigenic component, responsible for the formation of neutralizing antibodies that confer immunity. However, other mechanisms may be involved in protecting against the disease.

The rabies virus is widespread throughout the planet and attacks both domestic and wild mammals, including humans. It is found in the saliva and secretions of infected animals and is inoculated to humans when infected animals attack them and cause a bite lesion in humans. In addition, the virus can also be transfused when an individual who has a break in the skin (entry route of the virus) has contact with the salivary secretions of an infected animal.

The two types of clinical manifestations of rabies are divided into furious and paralytic. Furiosa is common in carnivorous mammalian reservoirs of the disease. Agitation, hyperactivity, hallucinations, confusion, and a host of other related symptoms occur. Paralytic rabies is common in rodents and cattle, but horses, goats, sheep, and pigs are also vulnerable.

Vectors

Rabies is a zoonosis caused by a virus of the Rhabdoviridae family. This disease affects all mammals located in three large ecological niches: aerial (bats), terrestrial (dogs, cats, mongooses, foxes, ferrets, raccoons, wolves) and marine.

The clues to know if a bat has rabies are:

• When they fly they usually hit each other.
• When they leave the day.
• When they fall to the ground.

In general, the other animals present abundant salivary secretion, which acts as a virus culture, and, in advanced stages, bleeding from orifices.

Transmission

A dog with anger, dropping saliva from his mouth.

Rabies is transmitted through bites or direct contact of mucous membranes or wounds with saliva from the infected animal. Acquisition through corneal transplantation from an undiagnosed rabies-infected dead donor, by aerosolization in caves contaminated with bat guano, or by laboratory personnel has also been documented. Although human-to-human transmission by bite has not been documented, the virus has been isolated from the saliva of rabies patients. This virus has also been identified in blood, milk, and urine. Transplacental transmission has not been documented. In 2009, data on contagion from atypical exposures from handling meat and offal of infected animals in kitchens were also presented.

The virus is excreted in the infected animal from five days after the clinical manifestations, although in the experimental model this period can be extended up to fourteen days before the onset of the disease.

The incubation period ranges from five days to a year, with an average of twenty days. There is some evidence of local replication of the virus in muscle cells at the wound site. However, it is possible that the virus spreads to the central nervous system without prior viral replication, through axons, to the brain, at a rate of 3 mm/h (in animal models), with replication exclusively in neuronal tissue..

Rabies is manifested by a prodromal period that lasts from two to ten days with nonspecific signs and symptoms such as fatigue, headache, fever, anorexia, nausea, vomiting, and paresthesias at the site of the wound, followed by difficulty swallowing., hydrophobia between 17% and 50% of cases, disorientation, visual or olfactory hallucinations, focal or generalized seizures, periods of excitability and aerophobia. In approximately 20% of cases, rabies can manifest as a flaccid paralysis. These clinical manifestations are followed by a period of coma, which results in death in the vast majority of cases.

This disease, if not treated with the utmost urgency, ends up causing the death of the patient. There is currently no specific treatment for patients with rabies. This disease is generally considered fatal. There are only isolated reports of survival with intensive care measures. When a person is infected, the symptoms of the disease can take between 60 and 300 days to manifest themselves.

Transmission is only possible through direct contact with a carrier vector or with biological material derived from it, since as it is a virus with a lipid envelope it is very sensitive to environmental factors (labile).

Epidemiology

Rabies is a disease with virtually universal distribution, with the exception of Australia, which affects both domestic and wild animals. In less industrialized countries, exposure to domestic animals (dogs and cats) constitute the major source of human rabies, unlike countries like the United States where wild animals (including bats) constitute the most important reservoir of rabies. The virus begins to be excreted in the infected animal from five days before the clinical manifestations.

The World Health Organization (WHO) manages data that corroborate that in some regions it is still a major public health problem, such as in some countries in Asia and Africa, where it causes more than 55,000 deaths a year, of which most of the victims are people under fifteen years of age. It is estimated that rabies causes 31,000 deaths a year in Asia, which represents 60% of deaths from this cause in the world.

In recent years, the number of cases has increased in China and Vietnam due to habitual human consumption, without proper hygienic and sanitary conditions, of dogs and cats. According to the latest statistics from 2007, in China, where less than 10% of dogs are vaccinated, 3,380 people died from rabies.

Pathology

In many cases, infected animals have variable behavior, are extremely violent and attack without apparent provocation.

The pathology in the human species is as follows:

• Infection by wound or bite. Previously, it was also transmitted by operations such as the cornea transplant.
• The virus has a first multiplication in the muscle cells, hence it passes to the neurons and finally to the nervous nodes.
• The place where the disease manifests most strongly is the brain (encefalitis). However, the time it takes to develop this stage is quite long and depends on many factors.
• Viruses begin to pass from neurons to others through synaptic contacts, which makes the immune system unable to detect them.
• From the brain you can travel through the nerves to anywhere in the body, causing a systemic infection.

Symptoms

Rabies disease.

Symptomatically, the patient goes through four phases:

1. Incubation phase: the incubation period of rabies is highly variable: from seven days to more than one year, with an average of one to two months. This variability depends on the number of inoculated viruses, the amount of tissue affected, the mechanisms of defense of the host and the distance that the virus has to travel between the inoculation site and the central nervous system.
2. Prodromal phase: lasts between two and ten days. Unspecific symptoms appear: fever, headache, general discomfort, myalgia, fatigue, anorexia, nausea and vomiting, pharyngeal pain, cough without expectation, parasesthesias or fasciculations at the site of inoculation.
3. Acute encephalitis phase: lasts between two and seven days. It is characterized by acute encephalitis whose symptoms are indistinguishable from other viral encephalitis. The patient can manifest excitation and agitation, mental confusion, hallucinations, aggressiveness, grotesque aberrations of thought, muscle spasms, meningism, opiates, convulsions, local paralysis, hyperestesia, photophobia, phenophobia or also referred to as lygirofobia, high fever, irregular midriasis, lagrimeo, hypoorrea, diaphobiasis,
4. Fase of rabbiic encephalitis: lasts between one and ten days. It is characterized by a functional disorder of the brain stem, which distinguishes the rage of other encephalitis and explains the rapid evolutionary deterioration of the patient. The involvement of cranial pairs produces diplopia, facial paralysis, optical neuritis and dysphagia. The combination of the dysphagia with the sialorrea produces the classic picture of "showing foams in the mouth". 50% of the cases have hydrophobia, which is characterized by a violent, involuntary and painful contraction of the diaphragm and the pharyngeal, laryngeal and respiratory muscles, triggered by the swallowing of fluids. The affectation of the amigdalino core generates priapism and spontaneous ejaculation. The patient ends up entering a coma and death occurs by apnea, by affecting the respiratory center of the brain.

From the second phase, it is fatal in 99.9% of cases. The only treatment option is to give immunoglobulins and to inject a vaccine against the virus, which is only effective during the incubation phase.

A sure diagnosis is post mortem. However, it can be diagnosed by microscopy thanks to the appearance of the so-called "Negri bodies" in the cells.

Differential diagnosis

• Encephalitis
• Epilepsy
• Malaria
• Transverse myelitis
• Poliomyelitis
• Psychosis
• Guillain-Barré syndrome
• Tetanus

Treatment

Almost all human exposure to rabies was fatal until Louis Pasteur and Émile Roux developed a vaccine in 1885. Their original vaccine was collected from infected rabbits, whose virus in nerve tissue was weakened by allowing it to spread. dry for five to 10 days. Similar vaccines derived from nerve tissue are still used in some countries, as they are much cheaper than modern cell culture vaccines.

The human diploid cell rabies vaccine began in 1967. Less expensive purified chicken embryo cell vaccines and purified vero cell vaccines are now available. A recombinant vaccine called V-RG has been used in Belgium, France, Germany, and the United States to prevent rabies outbreaks in non-domesticated animals. Pre-exposure immunization has been used in both human and non-human populations, where, as in many jurisdictions, domestic animals must be vaccinated.

The treatment of patients infected by the Rhabdoviridae virus consists first of an exhaustive washing with plenty of soap and water and timely hospital care. One dose of human rabies immune globulin (HRIG) should be given in addition to four doses of rabies vaccine given two weeks later. If a wound is present, the full dose of human rabies immunoglobulin should be applied, if possible, to the wound. The first dose of the vaccine is given at the same time, and the rest of the injections are given on days three, seven, and fourteen after the initial injection. People who have weakened immune systems may require a fifth dose of the vaccine.

A person who has been vaccinated against rabies and has been exposed to the rabies virus should receive two doses of the booster vaccine three days after exposure. These people do not need an injection of human rabies immune globulin.

Suturing the wound should be avoided because the Rhabdoviridae virus is anaerobic and closing it would favor its multiplication. The wound is closed if it affects the functioning of the compromised organ, if it is too extensive (it is sutured with 2-0 catgut making simple stitches separated between 1 and 2 cm) or if it affects areas such as the face, genitals or folds.

Regarding the application of tetanus toxoid, its efficacy has not been proven.

If the patient presents any type of neurological symptom, a coma should be induced, waiting for the response of the innate immune system and the activation of adaptive immunity mediated by T1 lymphocytes. It must be specified that in any of the cases death can occur due to cardiorespiratory arrest of central origin.

Post-exposure prevention measures

The rabies vaccine for humans is made on the basis of suckling mouse brain, which is applied in 2 ml doses. subcutaneously and periumbilically. In pregnant patients it is applied in the interscapular or deltoid region. The treatment is ten doses, in a scheme of seven doses in series, followed by three reinforcements: on the tenth, twentieth and sixtieth day counted from the last vaccination of the series.

1. Local soap and water wound asses; later, benzalconium chloride can be used at 1 %, iodine solutions at 5 % or alcohol 40 to 70%.
2. The suture of the wound should be different; otherwise, the wound must be infiltrated with anti-rabic or serum human gammaglobulin.
3. The administration of antibiotics and toxoid tetanus should be valued in each particular case.
4. Immunoprophylaxis. Hyperimmune serum or gammaglobulin and anti-rabic vaccine.

The post-exposure treatment contemplates the application of the anti-rabies vaccine only (reduced schedule 10 doses) or application of anti-rabies vaccine + anti-rabies serum (classic schedule 14 doses plus serum) and said schedule depends on the type of exposure and the condition of the animal aggressor.

Currently, the scheme of 5 doses on days 0,3,7,14 and 28 post-exposure has been approved.

Precautions in the application of immunoglobulin

1. The dose indicated for possible interference with the production of vaccine-induced antibodies should not be exceeded.
2. It should not be applied on the same site as the vaccine, or reuse the syringe.
3. It is not recommended in previously immunized individuals with diploid cell vaccine.

Both the serum and the gamma globulin provide immediate protection, lasting approximately 21 days.

Types of vaccines

• 1. Brain Vaccine of mouse lactating type Fuenzalida. It was introduced in 1956. It is prepared from the cultivation of inactivated rabies viruses with ultraviolet light in the brain of newborn mice. He's very immunogenic. A daily dose is recommended for 14 days of 0.5 ml in children under three years and 1 ml for adults, by subcutaneous means, in the periumbilical region or interescapulovertebral. In case of extensive injuries it is recommended to continue vaccination for up to 21 days. Secondary reactions are usually local, such as pain, erythema and induration on the application site, which occur up to 20% of cases and usually at the end of immunization.

It is estimated that 1 in 8,000 vaccine recipients may present some neurological complication such as encephalitis, transverse myelitis, peripheral neuropathy and neuritis. Complications are directly related to the number of vaccine doses and the age of the patient. In the event of any of these adverse reactions, this type of vaccine should be discontinued and the diploid cell vaccine continued with the scheme indicated in Table 13.

Steroids can be used in the management of severe, life-threatening reactions.

• 2. Pato embryo vaccine. It is obtained from the cultivation of rabies viruses in beta-propionolactone inactivated duck embryos; although it produces less adverse reactions than the mouse brain vaccine is less immunogenic, so it has been stopped using since 1982.

Neurological complications associated with the vaccine have been correlated with inadequate inactivation of the virus and in the initial vaccines with the presence of neuronal tissue.

• 3. Human diploid cell vaccines (VCDH). They are developed in human diploid cells; there are two types of these: WI-38 inactivated in tri-n-butyl-phosphate86 and MRC-5 inactivated in ownnolactone and developed in human fibroblasts. Other inactive virus vaccines have been developed in pulmonary diploid cells of Rhesus adsorbide monkey (VRA). Since 1976 these vaccines have been used in humans for prophylaxis of rabies pre and post-exposure worldwide.

• 4. Messenger RNA Vaccines. Studies have been conducted in laboratory animals with an anti-rabic vaccine based on messenger RNA technology with good results. Clinical studies have subsequently been initiated in humans where it has been proven that this type of vaccine induces the creation of antibodies against the rabies virus in humans. Research to obtain a vaccine based on this technology is developing.

Survivors

Seven cases of rabies survival have been reported worldwide. The first, that of patient Jeanna Giese, occurred after the patient had been induced into a coma. Through this process, the doctors were able to cure the disease in that particular case.

On April 10, 2008 in Cali (Colombia) a local newspaper reported that an 11-year-old boy could have recovered after a coma-inducing treatment. This boy was infected on February 15, 2008 when several children were bitten by a cat when mistreating it and trying to kill it, in Santander de Quilichao, a town near Cali. However, it was not possible to isolate the rabies virus from samples of saliva, hair and cerebrospinal fluid belonging to the surviving child that were sent to the Pasteur Institute in Brazil and the National Institute of Health in Bogotá, so some believe that he never suffered from the rabies virus. disease. Even so, the survival of 6 people infected from phase 2 of the disease has been verified, so the treatment of said protocol could be well underway.

In June 2013, Chilean César Barriga was bitten by a dog infected with rabies. After developing the symptoms of the disease, a coma was induced for a period of one month, after which he was able to recover, becoming the seventh world survivor of the disease, since records have been recorded.

Control of the suspicious animal

• 1. The animal (dog or cat) must be captured and kept in observation by a veterinarian for the next ten days.
• 2. In case the animal is sacrificed, special care must be taken for the proper preservation of the brain, in order to establish the definitive diagnosis of rabies.

The dog and the rabies

François Boissier de Sauvages de Lacroix, Della natura and causa della rabbia (Dissertation sur la nature et la cause de la Rage), 1777

Dogs are one of the species that transmit the virus to humans.

Urban rabies occurs mostly in areas with a high canine population density; For this reason, the most effective form of prevention to stop the cycle of viral transmission is massive vaccination campaigns, thus reducing the number of dogs susceptible to the disease. Bats are the main transmitters of wild rabies, making it more difficult to control.