Rabies

Introduction to rabies Rabies, or rabies, is an acute viral infection that attacks the central nervous system. All warm-blooded animals, including humans, may be infected. It is mostly obtained by biting animals. It is generally believed that mad dogs with white foam on the mouth bite into the infection. In fact, cats, white raccoons, raccoons, skunks, foxes or bats may also be sick and contagious. Diseased animals often become very savage, and the virus in the saliva enters the next patient from the bite wound. basic knowledge The proportion of illness: 0.0003% Susceptible people: no specific population Mode of infection: body fluid transmission contact propagation Complications: diabetes insipidus hypertension low blood pressure arrhythmia hypothermia respiratory alkalosis congestive heart failure thrombosis

Cause of rabies

Rabies virus infection (45%):

Rabies virus belongs to rhabdoviridae, lyssavirus, virus-like bullet, 75-80 nm in diameter, 175-200 nm in length, inner core is core shell, contains 40 nm core, outer layer is The dense capsule has many filamentous protrusions on the surface, the distal end of the protrusion is braided, and the whole virus has a honeycomb-like hexagonal structure. The genome of the virus is a negative-stranded single-stranded RNA with a molecular weight of 4.6×106, and the viral genome is long. 11932 nucleotides, of which about 91% of nucleotides are involved in encoding five known structural proteins, namely glycoprotein (GP), envelope matrix protein (M2P), shell matrix protein (M1P), nuclear protein ( NP) and transcriptase protein (LP), genomic RNA and 180 NP molecules bind to ribose nucleoprotein (RNP), which protects RNA from degradation and provides genomic replication and transcription. A suitable structural basis.

M2P is the smallest structural protein of rabies virus (molecular weight is only 25×103). It can connect to the outer membrane of the virus and the GP and nucleocapsid on the membrane. GP is a typical transmembrane glycoprotein that binds to the acetylcholine receptor to make the virus. It is neurotoxic, and can induce the production of neutralizing antibodies and stimulate cellular immunity in the host, and has a protective effect against rabies virus attack. NP is a group-specific antigen of rabies virus, which can produce complement-binding antibody, NP-induced anti-antigen. Rabies virus protection is produced by the interaction of various cytokines (such as antibodies, mononuclear factors and lymphocytes); it also promotes neutralizing antibodies, and rabies virus GP and NP may also induce interference in the body. Prime.

Immune-mediated damage (30%):

At present, it is believed that the local presence of the virus is not the only factor that causes the difference in clinical manifestations. The humoral immunity and cell-mediated immunity have a protective effect in the early stage. However, when the virus enters a large number of nerve cells, the immune-mediated damage and the onset also have a certain relationship. The immunosuppressed mice were delayed after vaccination with rabies virus. After passive input of immune serum or immune cells, the death accelerated. In human rabies, the lymphocytes positive for rabies virus cell proliferation were mostly arrogant, and the death was faster. Myelin basic protein (MBP) has an autoimmune response and is also a manic type, and the disease progresses rapidly. Immunological damage mediated by antibodies, complement and cytotoxic T cells can be seen in the brain tissue.

Source of infection (20%):

The virus can be inoculated into chicken embryos, rat brain, and cultured in hamster kidney cells and diploid cells. The virus isolated from humans and animals is a wild strain that exists in nature, and is also a disease of human or animal. The pathogen, called "street virus", is characterized by strong virulence and long incubation period (inoculation for 15 to 30 days in the brain), which can be propagated in the parotid gland, and can cause disease after infection in various ways. After the street virus is continuously passaged in the animal brain (more than 50 generations), the virulence is reduced, the incubation period is shortened, and it is fixed for 3 to 6 days. It loses pathogenicity to humans and dogs, does not invade saliva, and does not form an inner matrix. As a "fixed virus", although the fixed virus has attenuated mutation, it still retains its main antigenicity and can be used for the preparation of live attenuated rabies vaccine for vaccination.

The rabies virus is easily inactivated by ultraviolet light, formaldehyde, 50% to 70% ethanol, mercury chloride and quaternary amine compounds such as benzalkonium bromide. The suspension loses its vitality after 56 ° C for 30-60 min or 100 ° C for 2 min. It is not easy to be killed by phenol and cresol soap solution. It can be stored for several years under lyophilization. The infected tissue can be stored in 50% glycerol for inspection.

Pathogenesis

Rabies virus has a strong affinity for nerve tissue, mainly through nerve retrograde, centripetal to the central transmission, generally does not enter the blood.

2. Invasion of the central nervous system from the peripheral nerve The virus spreads to the heart along the axis of the peripheral nerve at a rate of about 5 cm/d. After reaching the dorsal root ganglion, it begins to multiply and then invade the spinal cord and then spread throughout the central nervous system. It mainly invades neurons in the brain stem and cerebellum, but it can also terminate in a certain part during the process of diffusion, forming a special clinical manifestation.

3. From the central nervous system to the various organs during the diffusion period, the virus spreads eccentrically from the central nervous system to the peripheral nerves, invading various tissues and organs, especially the parotid gland, tongue taste buds, olfactory nerve epithelium and other viruses, due to the vagus nerve nucleus, Damage to the swallowed nerve nucleus and hypoglossal nucleus can occur in respiratory muscles and swallowing tendons. Clinically, patients develop symptoms such as water-induced fear, difficulty breathing, and difficulty swallowing. Sympathetic nerves are stimulated to increase salivation and sweating; vagus nerve Section, sympathetic ganglia and damage to the heart ganglion can cause cardiovascular system dysfunction and even sudden death.

Rabies prevention

In view of the lack of effective treatments for this disease, preventive measures should be strengthened to control the spread of the disease. Vaccination has a positive value for preventing the disease, and strict implementation of dog management can significantly reduce the incidence.

(1) Manage the source of infection to kill all wild dogs, and register the hounds, police dogs and experimental dogs that must be kept, and do a good job of vaccination. When the sick cats are found, they will immediately kill them, so as not to hurt people and bite peoples homes. Dogs, domestic cats should try to capture and isolate for 10 days. Animals that are still alive can be determined to be quarantined by non-rabid animals. The dead animals should be examined for brain tissue and burned or buried. Peel or eat.

(2) Wound treatment in the early stage of wound treatment is extremely important. After being bitten, the wound should be thoroughly cleaned with 20% soapy water and wiped continuously. The deeper wound still needs to be inserted with a catheter and continuously perfused with soapy water. Washing, if there is immune serum, after the skin test is negative, it can be injected into the bottom and around the wound, and the wound should not be sutured or bandaged.

(3) The vaccination target is:

1 bitten by wolves, foxes, and other beasts;

2 being killed by the disease (including the observation period) or the dog whose whereabouts are unknown, the bite of the cat;

3 is a bite of an animal that has been killed and whose brain tissue has been corrupted;

4 skin wounds are sputum saliva stains;

5 wounds in the head, neck, or wounds larger and deeper, such as biting animals (referring to non-endemic areas) 5 days after the endangered, the injection can be suspended;

6 The medical staff's skin damage is contaminated by rabies patients. In recent years, some diseases have been found in the country where rabies is killed by bites, but the dog is safe and sound. It is confirmed that the dog's saliva is poisonous, so it is popular. In the area, dogs should be vaccinated. Table 1 shows the indications for rabies vaccination.

China has widely used voles kidney cell vaccine. Since 1979, Wuhan Bioproducts has passed the identification, put into operation, and mild bites have 2ml intramuscularly on the 0th, 7th and 14th day. Severe bites and head, face and neck. The bites were intramuscularly injected with 2 ml on days 0, 3, 7, 14 and 30.

The effects of the vaccine are inconsistent in the reports of some people, and some believe that the effect is only 1/6 of that of human diploid vaccine. Therefore, it is necessary to find a new generation vaccine.

The immune serum has anti-rabies horse serum and human anti-rabies globulin. The current production in China is 10 ml per animal, including 1,000 IU; the adult dose is 20 ml; the child is 40 IU/kg, which can be applied after the skin test is negative. Half dose is used for local wound injection, and the other half dose is intramuscular injection. The dose of human anti-rabies globulin is 20 IU/kg. The immune serum can interfere with the host's active immunity and affect antibody production. Therefore, it must be 10 after the end of the inoculation. A booster dose vaccine was administered on days 20 and 90 to trigger a recall response to produce a larger amount of the corresponding antibody.

(4) Other tetanus antitoxin or toxoid as needed, and suitable antibacterial drugs. Patients with neurological reactions after vaccination may be given adrenal cortical hormone, interferon and interferon inducer to protect animal infections. Whether human prevention is effective or not is subject to further clinical practice.

1. The animals inspected are limited to dogs and cats in non-endemic areas;

2. The bite in the endemic area should be fully vaccinated.

Rabies complications Complications diabetes insipidus hypertension hypotension arrhythmia hypothermia respiratory alkalosis congestive heart failure thrombosis

The main complications are increased intracranial pressure, hypothalamic involvement caused by excessive or too little antidiuretic hormone secretion (causing diabetes insipidus), autonomic dysfunction caused by hypertension, hypotension, arrhythmia (ventricular supraventricular tachycardia, Bradycardia, or even arrest) or hypothermia, common sputum, may be systemic or focal, respiratory dysfunction, such as hyperventilation and respiratory alkalosis are common in the prodromal and acute phases, and later occur Hypoxia, reported complications include congestive heart failure, acute renal failure, superior vena cava thrombosis, secondary infection of the lung or urinary system, and gastrointestinal bleeding.

Rabies Symptoms Common Symptoms Irritability, appetite, lack of bite healing wounds... Tidal breathing, drowsiness, difficulty breathing, nausea, "three fears" (water sound... high fever convulsions

The length of the incubation period is not one of the characteristics of the disease, most of them occur within 3 months, 4% to 10% for more than half a year, about 1% for more than one year, and the longest one for 10 years. The factors affecting the length of the incubation period are age (small children), wound site (early and facial onset), deep and shallow wounds (early onset), the number of virus invasions and the virulence of the strains. Expanded treatment and vaccination against rabies vaccine, etc. Others such as trauma, cold, overwork, etc. may promote early onset.

The clinical manifestations can be divided into two types: manic type (encephalitis type) and paralyzed type (static type), which are divided into the following three stages:

1. The prodromal phase of the two types of prodromal phase is similar. Most patients have low fever, lethargy, lack of appetite, a few nausea, vomiting, headache (more in the occiput), back pain, general discomfort, etc. before the onset of excitement. The sound, light, wind and other stimuli begin to be sensitive, and there is a sense of throat tightness. The early symptoms with significant diagnostic significance are the wounded parts and nerve pathways that have healed, numbness, itching, stinging or insect crawling, ants walking. Such sensation abnormalities occur in about 80% of cases, which is caused by virus reproduction stimulating neurons, especially sensory neurons. This symptom can last for several hours to several days, and this period lasts for 1 to 2 days, rarely exceeding More than 4 days.

2. The excitement period or the flood season can be divided into two types, and the performance of the two types is different.

(1) Manic rabies: the most common in the country, about 2/3 in foreign countries, the patient gradually enters a state of high excitement, which is characterized by extreme horror, a sense of horror in the face of the disaster, and very exciting for water, light, wind, etc. Sensitive, causing paroxysmal pharyngeal spasm, difficulty breathing, etc.

The fear of water is a special symptom of this disease, but not necessarily every case, not necessarily in the early stage. Typical drinking water, seeing water, smelling water, or only mentioning drinking water can cause severe throat muscle spasm. Therefore, the patient is extremely thirsty and does not dare to drink, even if drinking can not swallow, full of mouth drooling, staining the bed or vomiting around, because the vocal cords are stunned, so the words are unclear, hoarse, and even lost.

Afraid of the wind is also a unique symptom of the disease, breeze, hair, wearing a wind, etc. can lead to pharyngeal muscle spasm, other such as sound, light, touch, etc., can also cause the same episode.

The onset of pharyngeal tendon makes the patient extremely painful, not only unable to drink water and eat, but also often accompanied by assisted respiratory muscle spasm, resulting in difficulty breathing and hypoxia, or even a systemic painful convulsion. After each episode, the patient is still restless and has A lot of sweating and dehydration.

In addition, due to hyperactivity of the autonomic nerves, the patient developed excessive sweating, drooling, increased body temperature above 38 °C, increased heart rate, increased blood pressure, enlarged pupils, painful expression, and anxiety, but most of the mind was clear, and there was very little invasive behavior. As the state of excitement grows, some patients may experience symptoms such as mental disorders, paralysis, auditory hallucinations, and screaming, and the disease progresses rapidly. Most of them die of respiratory failure or circulatory failure during the episode. This period lasts 1 to 3 day.

(2) Paralytic rabies: India and Thailand are more common, accounting for about 1/3 of the total, less than 10 cases reported in China, no clinical excitement, no symptoms of phobia and difficulty in swallowing, but high fever, headache , vomiting, bite pain begins, followed by limb weakness, bloating, ataxia, partial or total muscle spasm, urinary retention or incontinence, showing cross-sectional myelitis or ascending spinal cord paralysis, early percussion Hammer slamming the chest muscles, can be seen slammed uplift, calmed down after a few seconds, early in the percussion only showed muscle edema and hair erection, the course lasted 4 to 5 days.

3. Two types of rabies in the coma or paralysis period are not easy to distinguish, the sputum stops, the patient is quiet for a while, there is fashion and can barely drink water to swallow, the reaction weakens or disappears, and turns into flaccid paralysis, among which the most common limb soft palate, the eye muscle , facial and chewing tendons, manifested as strabismus, eye movement disorders, mandibular fall, mouth can not close and face lack of expression, in addition, there are still a loss of voice, feeling loss, reflex disappearance, pupil dilated.

In this period, the patient's breathing gradually becomes weak or irregular, and there may be tidal breathing, rapid pulse rate, blood pressure drop, low heart sound, cold limbs, rapid death from respiratory and circulatory failure, and patients before dying. More into a coma, this period lasts 6 to 18h.

The entire course of rabies, including the prodromal period, averaged 8 days for manic episodes and 13 days for paralysis.

The lesions of manic rabies are mainly in the brain stem, the cervical nerve or higher part of the central nervous system, and the lesions of paralytic rabies are confined to the spinal cord and the medulla, thus causing differences in clinical symptoms.

In most cases, rabies caused by blood-sucking bats does not show excitement, and there is no pharyngeal spasm and water-sucking phenomenon, and the above-mentioned behavior is the main clinical manifestation.

Rabies check

1. The total number of white blood cells in blood, urine and cerebrospinal fluid ranges from (12 ~ 30) × 109 / L, the percentage of neutrophils is mostly above 80%, the percentage of large mononuclear cells can also be increased, and urine routine examination can often find light. Degree proteinuria, occasionally transparent cast, the pressure of cerebrospinal fluid is in the normal range or slightly increased, the protein is slightly increased, the number of cells is slightly increased, but rarely exceeds 200 × 106 / L, mainly lymphocytes.

2. Immunological test

(1) Determination of serum neutralizing antibody or fluorescent antibody: It has diagnostic value for uninjected vaccine, anti-rabies serum or immunoglobulin. The disadvantage is that it is difficult to detect before the 8th day of the disease, and the patient who has been vaccinated, such as When the antibody titer exceeds 1:5000, it is still valuable for the diagnosis of rabies. Because the vaccine is only low in antibody titer, ELISA is also used for antibody detection.

(2) Detection of rabies virus antigen: using fluorescent antibody to examine brain tissue smear, corneal print, frozen virus skin antigen, positive results can be obtained before onset, the method is simple, can be completed within a few hours, and with mice The intracerebral vaccination method has a high coincidence rate, so it is a kind of experiment with a large practical value. In an experienced laboratory, the reliability of the immunofluorescence test can reach more than 95%. Recently, it has been adopted. Rapid rabies enzyme immunological diagnosis (RREID) can be used to detect rabies virus antigen in brain tissue, which can be determined by visual observation or microplate reader. For example, the positive reaction shows orange color, and the negative reaction is negative. Colorless, very fast and easy.

3. Virus isolation Although the virus can be isolated from the brain tissue, spinal cord, parotid gland, lacrimal gland, muscle, lung, kidney, adrenal gland, pancreas and other organs and tissues, but the chances are not much, it is more difficult from cerebrospinal fluid and saliva. The virus is isolated; the longer the patient's survival time, the more difficult the virus is isolated. The isolated virus can be inoculated with tissue culture or animal, and the virus can be isolated and identified by neutralization test.

4. Inoculation and examination of brain tissue animals were carried out after death. Animals were inoculated into the brain of mice by making a 10% suspension of the brain tissue of the deceased (milk rats of 2 to 3 weeks old were sensitive to adult rats). The positive mice developed tremor within 6-8 days, vertical hair, tail straightness, paralysis and other phenomena, died within 10 to 15 days due to failure, and the nematode was found in the brain tissue sections of dead mice.

5. Reverse transcription polymerase chain reaction (RT-PCR) detection of rabies virus nucleic acid In order to detect most rabies virus and rabies-associated virus, the most conserved region of rabies virus nucleoprotein gene (N) can be selected to design primers: N1 ( (587) 5'-TTTTGAGACTGCTCCTTTTTG-3' (605), N2 (-) (1029) 5'-CCCATATAGCATCCTAC-3' (1013), take brain tissue or virus-infected cells, first obtain viral RNA, N1 primer for The cDNA was synthesized, and then subjected to a PCR reaction, and the result was detected by agarose gel electrophoresis.

The brain tissue of the deceased brain tissue or the bite of the human animal was used for pathological sectioning or tableting, and the Neisseria was examined by Seller staining and direct immunofluorescence, and the positive rate was up to 70%.

Routine X-ray, B-ultrasound, electrocardiogram, brain CT examination should be done routinely.

Diagnosis of rabies

diagnosis

In the case of an episode, the diagnosis may be preliminarily established according to the past history of rabies or suspected rabies or cats, wolves, foxes, etc. If you can understand the condition of the bite and the health of the animal, then Diagnosis of this disease is more valuable. If you are not sure whether the biting dog or cat is suffering from rabies, the animal should be kept in a cage. If the animal does not develop within 7 to 10 days, the animal can generally be excluded from rabies. The clinical symptoms such as excitement, arrogance, fear of water, fear of the wind, throat muscle spasm, a large number of sputum, sputum, etc., can make a clinical diagnosis of rabies, especially for those with obvious symptoms, whether there is "three fears" (fear of water, Light, wind) phenomenon, if necessary, using fan wind, pouring water and lighting test, madness symptoms are not obvious should pay attention to pharyngeal muscle edema and hair erection phenomenon, such as prenatal immunological antigen, antibody detection positive, post-mortem brain tissue animal inoculation and The discovery of the Neissular body in the cytoplasm of neurons can be confirmed.

Differential diagnosis

In some cases, the history of bite is not clear, and it is often misdiagnosed as neurosis in the early stage. After the onset, the symptoms are atypical, sometimes misdiagnosed as mental illness, tetanus, viral meningitis and leptospirosis, and quiet limb paralysis. Cases can be misdiagnosed as polio or Guillain-Barré syndrome. The latent period of tetanus patients is shorter, mostly 6 to 14 days. Common symptoms are closed jaws, bitter smile, and systemic muscle spasm lasts for a long time. There is a horned arch reversal, and rabies muscle spasm is intermittent, mainly in the pharyngeal muscle, tetanus patients are not highly excited and fear of water, active treatment can be cured.

Severe changes in consciousness (coma, etc.), meningeal irritation, cerebrospinal fluid changes and clinical outcomes may contribute to the identification of neurological diseases such as viral meningitis, immunological antigens, antibody detection, and virus isolation.

Rabies should be differentiated from rabies-like snoring (pseudorabies), which has a history of dogs and is often identified as a history of rabid bites or contact with diseased animals. Similar rabies occurs in hours or days. Symptoms, such as throat tightness, drinking water, mental excitement and other symptoms, but no fever, no drooling, not afraid of the wind, or showing drinking water, can not cause throat muscle spasm, such patients suggest, convince symptomatic treatment, can be very Get back to health quickly.

In addition, after Semple vaccination, complications involving the central nervous system may occur, which should be differentiated from rabies. The incubation period for patients with concurrent myelitis is 1 to 3 weeks after the start of the injection, and the shortest 6 days from the first injection. The longest person is 52 days. The clinical manifestation is sudden fever during the inoculation with ascending paralysis or incomplete transverse spinal cord disease. There are paraplegia and sphincter incontinence. If the diffuse meningitis is complicated, the onset is 5-8. Week, the clinical symptoms are headache, fever, viral infection, and myelitis. Both of the above complications are easily confused with paralytic rabies. The presence of neutralizing antibodies in cerebrospinal fluid is conducive to the diagnosis of rabies, dynamic observation during the course of disease, and The judgment of the efficacy of adrenocortical hormones is helpful for clinical identification. The death cases must rely on animal vaccination to make a diagnosis based on the presence or absence of the inner corpuscle and viral antigen.

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