How to Cite This Chapter: Rymer W. Rabies. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.18.1.22. Accessed April 13, 2024.
Last Updated: February 11, 2022
Last Reviewed: February 11, 2022
Chapter Information

Definition, etiology, pathogenesisTop

1. Etiologic agent: Rabies virus (RABV), a neurotrophic RNA virus of the Lyssavirus genus, Rhabdoviridae family. There are 8 genotypes of the virus; genotype 1 is viral strains isolated from most animals as well as laboratory strains used for vaccine production. Each genotype includes a number of RABV variants specific for individual animal species.

2. Pathomechanism: The virus infects the host’s wound and replicates in striated muscle cells. After up to >10 hours it penetrates to the peripheral nerve ends through binding to the nicotinic acetylcholine receptor in the postsynaptic membrane at the neuromuscular junction, and is then transported centripetally (through retrograde axonal transport) to dorsal root ganglia and cells of the spinal ventral horns. Finally it reaches the brain gray matter, where massive viral replication occurs, causing neuronal dysfunction. In the next step the virus spreads throughout the body through efferent sympathetic fibers and penetrates, among others, to salivary glands, lacrimal glands, cornea, and skin; it is found in nerves of the dermal papillae, blood vessels, lungs, liver, muscles, heart, kidneys, adrenal glands, and/or urinary bladder, and is present in saliva, tears, urine, airway secretions, and cerebrospinal fluid (CSF). Viral presence in saliva may precede clinical manifestations by 2 to 3 days. Histologic examination of cerebral tissue may reveal cytoplasmic inclusion bodies (the so-called Negri bodies), which contain virion components or whole virions. Absence of Negri bodies does not exclude rabies. Central nervous system inflammation is not pronounced, as the virus induces apoptosis of T cells migrating to the infected neurons.

3. Reservoir and transmission: The reservoir is mammals. In Europe the main reservoir for RABV and vector for its transmission is red fox (sylvatic rabies), but the virus is also transmitted by other wild mammals including martens, weasels, raccoon dogs, badgers, wild boars, and bats, and in North America also by striped skunks and raccoons. Farm animals develop rabies if bitten by an infected wild animal or hematophagous bats. Urban rabies, the main reservoir for which is dog, dominates in Southeast Asia, on the Indian subcontinent, and in Africa (see Epidemiology). Rabies can also develop following a cat or monkey bite. An increasing role in transmission is played by bats: insectivorous serotine bat (Eptesicus serotinus) and Daubenton bat (Myotis dasycneme) in Europe and pipistrellus (Pipistrellus spp) and hematophagous Desmodontidae (vampires, eg, Desmodus rotundus) in North America.

An individual acquires infection through a bite of a sick animal or an animal in the final phase of incubation. Moreover, virus transmission can occur when saliva comes into contact with a fresh wound, injured skin, or mucous membrane. Contraction of rabies through inhalation is also possible when staying in caves inhabited by bats. In such cases the virus penetrates through the conjunctiva or nasal mucosa to the olfactory nerve endings. Iatrogenic infection is possible as well, through tissue transplant from an individual with undiagnosed infection (most often through cornea transplant, but transmission via the vascularized organs, including the kidney and liver, has also been reported). Blood-borne transmission has not been reported (no documented viremia).

4. Risk factors: Close contact with animals, including traveling to countries with urban rabies transmission (especially low-cost travels), using local public transport, going on camping trips, bike trips, hiking, trekking, tramping, jogging, hunting, sleeping outdoors, cave penetration and climbing (contacts with bats: chiropterologists, cavers, speleologists); occupational exposure (veterinarians, forest district workers, laboratory workers who have contact with the infectious material). Skinning of nonexamined animals (shot, dead) may also lead to infection, especially when no surgical gloves are used. Children are at high risk of infection due to their natural need to pat, feed, and hug animals. The risk should also be considered in the case of direct contact with contents of live attenuated vaccines for animals.

5. Incubation and contagious period: The incubation period in humans is 9 days to 19 years, but it usually does not exceed 3 months and is shorter following head or neck bites. Animals may be contagious (have virus in their saliva) several days before the symptomatic phase of infection and remain contagious until death.


Rabies is an animal-borne neuroinfection with the highest mortality from among all infectious diseases. It is prevalent worldwide except for the Antarctic, New Zealand, Japan, and some islands. Two epidemic forms, sylvatic rabies and urban rabies, are distinguished. It is estimated that >50,000 of people (40% aged <15 years) die from rabies every year, predominantly in Asia and Africa. In Europe infections in humans are primarily imported.


There are 2 forms of rabies in humans: the furious form (with aggression, psychomotor agitation, and hypersensitivity to external stimuli) and the paralytic form. Prodromal symptoms are nonspecific and include malaise, headache, sleep disorders (insomnia or somnolence), and elevated body temperature. Typical presenting symptoms are paresthesias and pruritus or pain at the inoculation site, followed by anxiety, excitation, fear, irritability, and sometimes dejection. Moreover, neck pain, abdominal pain, nausea, vomiting, and diarrhea may also occur. The majority of patients infected through transplant of an infected cornea initially report retrobulbar pain. The prodromal period usually lasts 2 to 5 days.

The second stage of the disease is encephalitis with rich symptomatology. The altered mental status worsens and episodes of psychomotor agitation, visual and auditory hallucinations, focal or generalized seizures, tachycardia and other arrhythmias, respiratory disorders (most often hyperventilation), and/or high-grade cerebral fever occur. Agitation may develop spontaneously or be induced by acoustic, tactile, or visual stimuli. Between the episodes it is possible to establish contact with the patient, as the patient is calm and may even be aware of the disease. Autonomic nervous system dysfunctions cause sialorrhea, lacrimation, excessive sweating, pilomotor reaction (goosebumps), dilated pupils, or anisocoria. Aversion to swallowing saliva is present; the patient refuses to drink. Hydrophobia, a pathognomonic symptom of furious rabies, is caused by fear of a sudden, extremely painful jerking contraction of the diaphragm and accessory respiratory muscles initiated by swallowing. Stimuli such as turning the light on, seeing a leaking tap, hearing a sudden sound or noise, or draft also cause agitation and evoke jerking contractions of the diaphragm. Fear of a gust of wind or draft of air (anemophobia, aerophobia) is typical. Agitation episodes followed by generalized seizures may lead to respiratory and cardiac arrest. Paresis and flaccid paralysis, endocrine disorders (diabetes insipidus), electrolyte, fluid, and acid-base balance disorders, and sometimes intermittent hyperthermia and hypothermia occur. Amygdala involvement may cause priapism and spontaneous ejaculation. In end-stage disease the patient is in coma with predominant brainstem disorders. Hematemesis may occur and multiorgan failure progresses. The majority of patients die within 10 days from the onset of encephalitis symptoms.

Paralytic rabies accounts for 20% of all rabies cases. The disease has no agitation phase, and the clinical picture includes muscle weakness, progressive paresis and flaccid paralysis spreading symmetrically or asymmetrically, often of ascending type resembling Guillain-Barré syndrome, as well as fasciculations and loss of tendon reflexes. Statistically, patients with paralytic rabies survive several days longer compared with those with furious rabies.


Diagnostic Tests

Identification of the etiologic agent:

1) Virus detection is possible in the saliva, CSF, urinary sediment, central and peripheral nervous system, nasopharyngeal and bronchial secretions, and solid organs (RABV has not been identified in feces or blood).

a) Direct immunofluorescence assay is routinely performed to identify viral antigens; immunoenzymatic methods are also used. The specimens are supravital (brain tissue collected by trepanopuncture, corneal impression, nerve fibers in skin specimens from the neck at the hairline level (≥10 hairs) or are collected post mortem.

b) Real-time polymerase chain reaction (RT-PCR) is a highly sensitive and specific test performed in reference centers to detect viral RNA in the investigated material (skin specimen, brain bioptate, CSF, saliva, skin papilla).

c) Histologic examination of brain tissue allows for the detection of Negri bodies that are pathognomonic for rabies; they are most easily detected in the Ammon horn (hippocampus) and in the Purkinje cells in the cerebellum.

2) Virus isolation in cell culture or with the use of laboratory animals (inoculation using brain tissue, saliva, or CSF from an infected person).

3) Serologic test: Specific neutralizing antibodies are present in blood and CSF late, sometimes after a week since the onset of clinical symptoms. Detection of specific IgM and IgG in the CSF or serum of a nonvaccinated individual confirms the disease. In previously vaccinated individuals the presence of specific antibodies can be due to vaccination, therefore a repeat test is recommended. An increase in antibody titer may indicate the disease.

Diagnostic Criteria

Suspected case: Detection of encephalitis symptoms, including pathognomonic symptoms such as hydrophobia, anemophobia/aerophobia, tingling and pain at the bite site.

Probable case: A suspected case with a history of contact with an animal suspected to be rabid or diagnosed with rabies.

Confirmed case: The World Health Organization (WHO) recommends that each case of clinically suspected rabies should be confirmed by the presence of ≥1 of the following laboratory criteria:

1) Detection of viral antigens by direct immunofluorescence method (eg, corneal impression).

2) Virus isolation in cell culture or with the use of laboratory animals.

3) Detection of specific antibodies in the CSF or serum of a nonvaccinated person.

4) RT-PCR detection of viral RNA in supravital specimens or post mortem.

Differential Diagnosis

1. Furious rabies: Infection of the nervous system of other etiology (particularly herpesviral encephalitis); tetanus; delirium tremens; dissociative disorders and other psychiatric syndromes; simulating; intoxication with strychnine, phenothiazine, atropine compounds, or Cannabis indica.

2. Paralytic rabies: Guillain-Barré syndrome, poliomyelitis, transverse myelitis, Landry ascending flaccid myelitis.


Antiviral Treatment

None (the available antiviral medications are ineffective).

Symptomatic Treatment

Opioid analgesics, anticonvulsants, sedative and hypnotic agents, as well as induced coma (Milwaukee protocol).


Bacterial superinfections.

Special considerationsTop

Individuals who died from a neuroinfection or without an established confirmed diagnosis as well as those who returned from countries with urban rabies transmission within the last 6 months cannot donate tissues or solid organs.


Mortality is 100%. Only 1 fully documented case of rabies survival has been described to date, in a patient bitten by a bat, in whom the Milwaukee protocol was implemented.


Specific Prevention

1. Immunoprophylaxis: see Vaccines: Rabies.

2. Postexposure prophylaxis: see Vaccines: Rabies.

Nonspecific Prevention

1. Avoiding animal bites (among others, not provoking animals). Following a bite the animal (cat or dog) should be subjected to a veterinary follow-up for 15 days.

2. Postexposure prophylaxis: Wash the wound under running water immediately (for ~15 min), then use a disinfectant (eg, 40% ethyl alcohol solution, povidone-iodine iodopovidone, 0.1% iodine water solution, 20% soap solution, quaternary ammonium bases). Do not suture the wound directly after the bite. Remember to use postexposure tetanus prophylaxis (see Vaccines: Diphtheria and Tetanus).

3. Patient isolation: The patient should stay in a soundproof, darkened isolation room with restricted access of external stimuli.

4. Personal protective equipment (PPE) for medical staff: The staff taking care of a patient with rabies should wear protective gloves; gown; and eye, mouth, and nose protection. Saliva, CSF, tissue specimens, and other materials collected for diagnostic tests should be treated as infectious.

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