| disease | Rabies |
| alias | Hydrophobia, Hydrophobia, Rabies |
Rabies is an acute infectious disease caused by the rabies virus, which is zoonotic and commonly found in carnivorous animals such as dogs, wolves, and cats. Humans are usually infected through bites from rabid animals. Clinical manifestations include characteristic hydrophobia (fear of water), aerophobia (fear of drafts or wind), pharyngeal muscle spasms, and progressive paralysis. The symptom of hydrophobia is particularly prominent, hence the disease is also known as hydrophobia.
bubble_chart Epidemiology
This disease exists in more than 60 countries, with particularly high incidence rates in Southeast Asian nations. The domestic incidence ranges from 0.4 to 1.58 per 100,000, showing a significant increase. The number of deaths has risen to the first or second position among statutory pestilence diseases.
The primary source of pestilence domestically is rabid dogs, accounting for 80–90% of human rabies transmissions. However, in some areas, the virus-carrying rate among "healthy dogs" can exceed 17%, which warrants attention. Pigs, cats, and cattle also play significant roles in China. Wolves (Eastern Europe), mongooses (South Africa, the Caribbean), foxes (Western Europe), and vampire bats (Latin America) serve as pestilence sources in their respective regions.
In terms of transmission modes, it can be divided into urban-type, spread by unvaccinated dogs and cats, and forest-type, caused by skunks, foxes, raccoons, mongooses, wolves, and bats.
The saliva of rabid dogs, cats, and other animals contains a high concentration of the virus, which enters the body through bite wounds. Mucous membranes also serve as entry points; humans can become infected if the conjunctiva is contaminated by the saliva of a rabid animal or if the anal mucosa is licked by a rabid dog. Additionally, infection may occasionally occur through skinning rabid animals, consuming contaminated meat, or inhaling virus-laden aerosols in bat-populated caves.
Humans are generally susceptible to the rabies virus, with hunters, veterinarians, and animal handlers being at higher risk. Rural adolescents have more contact with rabid animals, leading to higher infection rates. The disease occurs year-round in tropical and subtropical regions, while in northeastern China, it is more prevalent in spring and summer.The average incidence rate after a bite from a rabid dog is 15–20%, and from a rabid wolf, 50–60% (both figures refer to those who did not receive preventive vaccinations). Whether infection occurs depends on the following factors: 1. **Bite location**: Bites to the head, face, neck, or fingers have a higher disease mechanism. 2. **Severity of the wound**: Deep and large wounds have a higher infection rate, with deep facial wounds reaching around 80%. 3. **Local treatment**: Thorough and prompt cleaning of the wound reduces the disease mechanism. 4. **Clothing thickness**: Thicker clothing in winter lowers the chance of infection. 5. **Vaccination status**: Timely, complete, and adequate rabies vaccinations result in lower infection rates. Domestic reports show a post-vaccination incidence rate of 0.15% (compared to 0.016–0.48% abroad), while incomplete vaccination leads to a 13.93% incidence rate.
The rabies virus is an RNA-type rhabdovirus, with one end rounded and convex and the other flat and concave, resembling a bullet in shape. It has a diameter of 65–80 nm and a length of approximately 130–240 nm. The virus is easily inactivated by sunlight, ultraviolet radiation, formaldehyde, mercuric chloride, quaternary ammonium compounds (such as benzalkonium bromide), lipid solvents, and 50–70% alcohol. Its suspension can be inactivated by heating at 56°C for 30–60 minutes or at 100°C for 2 minutes. The virus can remain viable for several years when stored at -70°C or freeze-dried and kept at 0–4°C. Infected tissues can be preserved in 50% glycerol for testing.
Most animal experiments have shown that viremia does not occur during the incubation period or the onset of the disease. The pathogenesis of rabies can be divided into three stages.
(1) Local tissue proliferation phase: After the virus invades through the bite site, it aggregates and proliferates in the muscle spindle receptors and nerve fibers of the striated muscles at the wound, then invades nearby peripheral nerves. The interval from the local wound to invasion of the surrounding nerves is generally within 3 days, although some suggest the virus may remain at the invasion site for up to 2 weeks or even longer (accounting for most of the incubation period).
(2) Invasion of the central nervous system phase: The virus spreads centripetally along the axoplasm of peripheral nerves at a rate of approximately 3 mm per hour. Upon reaching the dorsal root ganglia, the virus proliferates extensively there before invading the spinal cord and the entire central nervous system, primarily affecting neurons in areas such as the brain and cerebellum.
(3) Spread to various organs phase: The virus spreads centrifugally from the central nervous system to peripheral nerves, invading various tissues and organs. Particularly, damage to the salivary nuclei, glossopharyngeal nuclei, and hypoglossal nuclei can clinically manifest as hydrophobia, difficulty breathing, and difficulty swallowing. Increased saliva secretion and sweating result from stimulation of the sympathetic nerves. Damage to the vagal ganglia, sympathetic ganglia, and cardiac ganglia can lead to cardiovascular dysfunction or sudden death in patients.
The pathological changes primarily consist of acute diffuse encephalomyelitis, particularly severe in the dorsal root ganglia and spinal cord segments corresponding to the bite site, as well as in the hippocampus, medulla oblongata, pons, and cerebellum. The meninges usually show no pathological changes. The brain parenchyma exhibits congestion, edema, and minor hemorrhages. Microscopically, nonspecific degenerative and inflammatory changes can be observed, such as vacuolation of neurons, hyaline degeneration, chromatolysis, and perivascular mononuclear cell infiltration.
All the above lesions are nonspecific. However, in 80% of patients, a specific and diagnostically significant eosinophilic inclusion body, called Negri body, can be found in the cytoplasm of neurons. Negri bodies are round or oval, measuring about 3–10 nm in diameter, with smooth margins and containing 1–2 small dot-like structures resembling cell nuclei. They are most commonly found in the neurons of the hippocampus and cerebellar Purkinje tissue. They can also be detected in the pyramidal cell layer of the cerebral cortex, spinal cord neurons, posterior horn ganglia, the neuronal layer of the retinal membrane, and sympathetic ganglia. Negri bodies are actually colonies of the virus, and under electron microscopy, rod-shaped viral particles can be seen within them.
The salivary glands are swollen and soft, with marked degeneration of acinar cells and mononuclear cell infiltration around the glandular tissue. Acute degeneration can also occur in pancreatic acini and epithelium, gastric mucosal parietal cells, adrenal medullary cells, and renal tubular epithelial cells.
bubble_chart Clinical Manifestations
The incubation period varies in length, with most cases occurring within 3 months, and the average reported domestically is 66.9 days. In 4–10% of patients, the incubation period exceeds half a year, and in 1%, it surpasses one year. The longest documented case in the literature is 19 years. The duration of the incubation period is related to factors such as age (shorter in children), the site of the wound (bites to the head and face result in earlier onset, averaging 39 days, while bites to the lower limbs have an average incubation period of 90 days), the depth of the wound (deeper wounds lead to a shorter incubation period), the quantity and virulence of the invading virus (higher virulence shortens the incubation period), among others. Other factors, such as incomplete wound debridement, trauma, exposure to cold, or excessive fatigue, may also precipitate the disease.
The clinical course of a typical case can be divided into the following three stages.
(1) Prodromal or Invasive Stage: Before the onset of excitement, most patients experience low-grade fever, loss of appetite, nausea, headache (often in the occipital region), fatigue, and general malaise, closely resembling a "common cold." Subsequently, they develop fear and restlessness, heightened sensitivity to sound, light, wind, and pain, and a sensation of throat tightness. A diagnostically significant early symptom is abnormal sensations at or near the wound site, such as numbness, itching, pain, or a crawling sensation, caused by viral replication stimulating neurons. This occurs in 80% of cases. This stage lasts 2–4 days.
(2) Excitement Stage: The patient gradually enters a state of heightened excitement, characterized by extreme terror, hydrophobia, fear of wind, episodic pharyngeal muscle spasms, difficulty breathing, urinary and fecal retention, and profuse sweating and drooling.
Hydrophobia is a hallmark symptom of the disease, caused by pharyngeal muscle spasms, though it may not appear in every case or may not manifest early. In typical cases, the sight, sound, or even mention of water—such as water from a river—or attempting to drink can trigger severe pharyngeal muscle spasms. Despite extreme thirst, the patient dares not drink and cannot swallow even if they try. Hoarseness and dehydration are common.
Fear of wind is another common symptom, where even a light breeze can induce pharyngeal muscle spasms. Other stimuli, such as light, sound, or touch, can provoke similar episodes. In severe cases, painful spasms may occur throughout the body. Respiratory muscle spasms often lead to difficulty breathing and cyanosis.
Sympathetic hyperactivity is frequently observed, manifesting as increased salivation, great dripping sweating, tachycardia, and elevated blood pressure and body temperature. Sphincter dysfunction resulting in difficulty urinating or defecating is also quite common.
Most patients remain lucid, experiencing extreme fear and dysphoria, but rarely exhibit aggressive behavior. As the excitement intensifies, some patients may develop mental disturbances, delirium, hallucinations, or episodes of thrashing and screaming. The disease progresses rapidly, and many patients die from respiratory or circulatory failure during these episodes. This stage lasts 1–3 days.
(3) Paralytic Stage: Spasms cease, and the patient becomes calmer, but flaccid paralysis sets in, particularly affecting the limbs. Muscles of the eyes, face, and jaw may also be involved, presenting as strabismus, uncoordinated eye movements, a drooping jaw, inability to close the mouth, and an expressionless face.
The patient's breathing becomes progressively weaker or irregular, and Cheyne-Stokes respiration may appear. The pulse grows thready and rapid, blood pressure drops, reflexes disappear, and the pupils dilate. Death from respiratory or circulatory failure occurs swiftly. Most patients lapse into unconsciousness before death. This stage lasts 6–18 hours.
The entire course of rabies generally does not exceed 6 days, though rare cases may extend beyond 10 days.
In addition to the typical cases mentioned above, there is also a "paralytic type" or "silent type" primarily characterized by paralysis, also known as "dumb rabies," accounting for approximately 20%. Patients with this type do not exhibit an excitement phase or hydrophobia but instead present with high fever, headache, vomiting, and pain at the bite site initially, followed by limb weakness, abdominal distension and fullness, ataxia, muscle paralysis, and urinary incontinence, among other symptoms, resembling transverse myelitis or ascending spinal paralysis. The lesions are confined to the spinal cord and medulla oblongata without involving the brainstem or higher regions of the central nervous system. The course of the disease can last up to 10 days, ultimately leading to death due to respiratory muscle paralysis and bulbar paralysis. Rabies caused by vampire bat bites often falls into this category.
bubble_chart Auxiliary Examination
(1) Blood, urine routine, and cerebrospinal fluid The total white blood cell count in peripheral blood ranges from 12,000 to 30,000/mm3, with neutrophils generally accounting for over 80%. Routine urine tests may reveal grade I proteinuria, occasionally with hyaline casts. Cerebrospinal fluid pressure may be slightly elevated, with a modest increase in cell count, usually not exceeding 200/mm3, predominantly lymphocytes. Protein levels may rise to over 200mg/dL, while glucose and chloride levels remain normal.
(2) Immunological tests Serum neutralizing antibodies are detectable 6 days after the onset of illness. By day 8, 50% of sera test positive, and by day 15, all sera are positive. Post-vaccination neutralizing antibody titers are mostly <10 IU, whereas clinical patients may reach 640 IU.
(3) Virus isolation There are two approaches: biopsy and autopsy. The former involves isolating the virus from salivary glands, brain biopsies, cerebrospinal fluid, and urine sediment, with brain tissue yielding the highest positivity rate. During autopsy, positive cultures can be obtained from the bite site, pericardium, adrenal glands, pancreas, liver, etc.
(4) Animal inoculation and Negri body examination Both are performed postmortem. A 10% brain tissue suspension is inoculated into the brains of 2-3-week-old suckling mice. Positive cases show symptoms such as tremor, piloerection, tail rigidity, and paralysis within 6-8 days, leading to death from exhaustion within 10-15 days. Negri bodies can be detected in the mouse brains.
Pathological sections or smears of the deceased's brain tissue or the biting animal's brain tissue are examined using Seller staining and direct immunofluorescence for Negri bodies, with a positivity rate of approximately 70%.
Early misdiagnosis is common, especially in children and those with unclear bite histories. For patients in the active stage, diagnosis can be made based on a history of dog or cat bites, confirmation of rabies in the biting animal, and prominent clinical symptoms such as paresthesia at the bite site, agitation, hydrophobia, aerophobia, throat spasms, profuse salivation, excessive sweating, and various forms of paralysis. A positive immunofluorescence test confirms the diagnosis definitively. When necessary, examination for Negri bodies in brain tissue or animal testing may be performed.
bubble_chart Treatment Measures
(1) Strict single-room isolation with dedicated nursing care, ensuring complete bed rest and avoiding all auditory, visual, and wind stimuli. Perform high-nutrition therapy via large vein catheterization, and medical staff must wear masks, isolation gowns, and gloves. The patient's secretions, excretions, and contaminated items must be rigorously disinfected. Install bed rails to prevent injury during convulsive episodes.
(2) Actively manage symptoms and prevent complications.
1. **Nervous System**: For patients with hydrophobia, enforce fasting and prohibit drinking, minimizing all stimuli. Administer phenytoin or diazepam for convulsions. For cerebral edema, use mannitol and furosemide as dehydrating agents; if ineffective, perform lateral ventricle drainage.
2. **Pituitary Dysfunction**: Restrict fluid intake for those with excessive antidiuretic hormone; for diabetes insipidus, provide intravenous fluids and administer vasopressin (Pitressin).
3. **Respiratory System**: Perform tracheotomy for dyspnea; administer oxygen and artificial respiration for cyanosis, hypoxia, or pulmonary collapse. For pneumonia, provide physiotherapy and antibiotics. Perform lung re-expansion for pneumothorax. Prevent aspiration pneumonia.
4. **Cardiovascular System**: Most arrhythmias are supraventricular—administer oxygen if related to hypoxemia; treat as myocarditis if viral. Use vasoconstrictors and volume expansion for hypotension. For heart failure, restrict fluids and administer digoxin. For stirred pulse or venous thrombosis, replace the venous catheter; remove it if superior vena cava obstruction occurs. Perform resuscitation for cardiac arrest.
5. **Others**: Transfuse blood for anemia and gastrointestinal bleeding. Use cooling blankets for high fever and heating blankets for hypothermia. Adjust fluid volume promptly for hypovolemia or hypervolemia.
The fatality rate is nearly 100%, with patients typically succumbing to respiratory or circulatory failure within 3 to 6 days. In recent years, there have been reports of a few cured cases, so every effort should be made to maintain respiratory and circulatory system functions and actively carry out rescue measures.
Given the lack of effective treatment for this disease, preventive measures should be strengthened to control its spread. Vaccination has proven value in preventing the onset of the disease, and strict management of dogs can significantly reduce the incidence rate.
(1) Management of the pestilence source: All stray dogs should be captured and killed. Hunting dogs, police dogs, and laboratory dogs that must be kept should be registered and vaccinated. Sick dogs or cats should be immediately killed to prevent harm to humans. Domestic dogs or cats that have bitten people should be captured and isolated for observation for 10 days. Animals that remain alive can be confirmed as non-rabid and released from isolation. For deceased animals, their brain tissue should be collected for examination and then incinerated or buried deeply; under no circumstances should the skin be peeled or the meat consumed.
(2) Wound treatment: Early wound treatment is extremely important. After being bitten, the wound should be promptly and thoroughly washed with 20% soapy water, with continuous scrubbing. For deeper wounds, a catheter should be inserted to allow continuous irrigation with soapy water. If immune serum is available, it can be injected into the base and surrounding areas of the wound after a negative skin test. The wound should not be sutured or bandaged.
(3) Vaccination: Vaccination is indicated for: ① those bitten by wild animals such as wolves or foxes; ② those bitten by dogs or cats that subsequently die (including during the observation period) or go missing; ③ those bitten by animals that have been killed or whose brain tissue has decomposed; ④ those with skin wounds contaminated by rabies saliva; ⑤ those with wounds on the head, neck, or large and deep wounds—if the biting animal (in non-endemic areas) remains healthy after 5 days, vaccination can be discontinued; ⑥ medical personnel with broken skin contaminated by rabies patients. In recent years, cases have been reported in China where individuals bitten by dogs died of rabies while the dogs remained healthy, and it was confirmed that the dogs' saliva carried the virus. Therefore, all individuals bitten by dogs in endemic areas should be vaccinated. Table 11-8 shows the indications for rabies vaccination.
Currently, rabies vaccines used worldwide are listed in Table 11-9.
In China, the hamster kidney cell vaccine is widely used. Since 1979, it has been certified and produced by the Wuhan Institute of Biological Products. For grade I bites, 2 ml is intramuscularly injected on days 0, 7, and 14. For grade III bites and bites on the head, face, or neck, 2 ml is intramuscularly injected on days 0, 3, 7, 14, and 30.
Reports on the efficacy of this vaccine vary, with some suggesting its effectiveness is only one-sixth that of human diploid cell vaccines. Therefore, there is a need to develop a new generation of vaccines.
Immune sera include equine anti-rabies serum and human anti-rabies immunoglobulin. Currently, China produces the former, with each vial containing 10 ml and 1,000 IU. The adult dose is 20 ml, while the pediatric dose is 40 IU/kg. It should only be used after a negative skin test, with half the dose injected locally around the wound and the other half intramuscularly. The single dose of human anti-rabies immunoglobulin is 20 IU/kg. Immune serum may interfere with the host's active immunity and antibody production, so booster doses of the vaccine must be administered on days 10, 20, and 90 after vaccination to trigger a recall response and produce a larger quantity of corresponding antibodies.
(4) Others: Tetanus antitoxin or toxoid and appropriate antibiotics should be administered as needed. For those who develop neurological reactions after vaccination, adrenal corticosteroids can be given. Interferon and interferon inducers have shown protective effects in animal experiments, but their efficacy in human prevention requires further clinical practice.
Table 11-8: Indications for rabies vaccination
| Exposure Method | Observation of Biting Animal* | Treatment | |
| When biting | During the 10-day observation period | ||
| Licking skin; abrasions or scratches; Grade I bite (bitten areas are arms, torso, and legs covered by clothing) | 1. Suspected rabies | Healthy | Start vaccination immediately and stop injections if the animal remains healthy after 5 days |
| Died of rabies | Start vaccination immediately and add immune serum if confirmed as rabies | ||
| 2. Confirmed rabies; biting animal is a wolf, fox, etc.; biting animal cannot be observed (killed or missing) | Vaccination + immune serum | ||
| Licking mucous membranes; Grade III bite (multiple wounds or bites on the head, face, neck, fingers, etc.) | Suspected or confirmed rabies animal is a dog, cat, or wild animal, or the biting animal cannot be observed | Vaccination + immune serum | |
*1. Observation animals are limited to dogs and cats in non-endemic areas. 2. In endemic areas, all bite victims should receive full preventive injections.
Table 11-9 Vaccines in Use and Under Evaluation Worldwide
| Vaccine Type | Countries Using (Developing) |
| Human Diploid Cell Vaccine | USA, France, etc. |
| Purified Chick Embryo Cell Vaccine | Argentina |
| Duck Embryo Vaccine | Switzerland, etc. |
| Hamster Kidney Cell Vaccine | China |
| Adsorbed Vaccine (RNA) | USA, etc. |
| Purified Verv Vaccine | France |
Inappropriate antidiuretic hormone secretion may occur, potentially complicated by pneumonia, pneumothorax, mediastinal emphysema, arrhythmia, heart failure, arteriovenous thrombosis, superior vena cava obstruction, upper gastrointestinal bleeding, acute renal failure, etc.
This disease needs to be differentiated from tetanus, viral meningoencephalitis, poliomyelitis, etc. Tetanus has a short incubation period, with trismus and opisthotonus but no hydrophobia symptoms. Poliomyelitis shows no hydrophobia symptoms, has prominent muscle pain, and most other symptoms subside during paralysis. Viral meningoencephalitis presents with severe mental changes and meningeal irritation signs; cerebrospinal fluid findings, immunological tests, and virus isolation all aid in differentiation.
Rabies-like hysteria patients may experience throat tightness, inability to drink, and excitement at varying intervals after an animal bite, but without fear of wind, salivation, fever, or paralysis. They often recover quickly with suggestion, persuasion, and symptomatic treatment.
After rabies vaccination, symptoms such as fever, joint soreness, limb numbness, ataxia, and various types of paralysis may occur, which are difficult to distinguish from the paralytic form of this disease. However, the former mostly recover after discontinuing vaccination and using adrenal corticosteroids. Fatal cases require confirmation through immunofluorescence tests or detection of Negri bodies in brain tissue.
