Rabies

Rabies is a neurotropic virus transmitted through the bite of an infected animal. The virus enters via the animal saliva, traveling along peripheral nerves to the central nervous system (CNS). The onset of nonspecific flu-like symptoms begins after an incubation period of 4–12 weeks, progressing to acute rabies encephalitis. Clinical features include fever, hydrophobia, hypersalivation, stupor, and mania, followed by coma and death resulting from respiratory and circulatory collapse. Paralytic rabies, a less common form, manifests with ascending paralysis that resembles Guillain-Barré syndrome. Rabies is preventable with rabies postexposure prophylaxis (PEP) and proper wound care but is almost always fatal once symptoms appear. Rabies preexposure prophylaxis (PrEP) is recommended for those at increased risk of exposure (e.g., veterinarians and travelers to endemic areas).

• Found in animal reservoirs in most countries throughout the world
• Considerable divide between developed and developing countries in terms of human deaths due to rabies
  • Incidence worldwide: ∼ 60,000 people die of rabies each year. [1]
  • Incidence in the US: Three people on average die of rabies each year.

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen
  • Rabies is caused by several different members of the Rhabdoviridae family.
  • Rhabdoviruses are rod or bullet shaped
  • Genus: Lyssavirus
  • ssRNA
• Transmission [2]
  • Most common animal reservoir worldwide: dogs (≥ 90%)
  • Most common animal reservoirs in the US: bats, raccoons, skunks, and foxes
  • Spread through saliva of rabid animal after bite injury
  • Via aerosols (e.g., bat caves); rare

• Rabies virus binds the ACh receptor of peripheral nerves in the bite wound → migrates retrogradely along the axonal microtubules (using motor protein dynein) → enters the CNS → infects the brain [3]
  • Diencephalon, hippocampus, and brainstem are involved first
  • Causes acute, progressive, and fatal encephalitis → encephalitic rabies
  • Causes ascending flaccid paralysis → paralytic rabies

General

• Incubation period: 4–12 weeks average [1]
• Prodromal symptoms
  • Flu-like symptoms (e.g., fever, malaise)
  • Pain, paresthesia, and pruritus near the bite site

Encephalitic rabies (∼ 80% of cases) [2]

• Hydrophobia: Rabies patients experience involuntary, painful pharyngeal muscle spasms when trying to drink; later on in the disease, the sight of water alone may provoke nausea or vomiting.
• CNS symptoms
  • Anxiety, agitation, and combativeness alternating with calm periods
  • Confusion and hallucinations
  • Photophobia
  • Fasciculations
  • Seizures
  • ↑ Muscle tone and reflexes with nuchal rigidity
• Autonomic symptoms (e.g., hypersalivation, hyperhidrosis)
• Coma and death within days to weeks of the development of neurological symptoms

Paralytic rabies (∼ 20% of cases) [2]

• Flaccid paralysis, gradually ascending and spreading from bite wound [4]
• Paraplegia and loss of sphincter tone
• Respiratory failure and death

The pathognomonic feature of rabies is hydrophobia due to pharyngeal muscle spasm. This may present along with agitation, strange behavior, mental status changes, and possibly foaming at the mouth.

Suspect rabies in patients with potential exposure and clinical features of rabies.

Antemortem diagnosis [2]

Several tests using multiple specimens must be performed because virus and antibody detection vary throughout disease. Identifying rabies virus antigen or nucleic acid confirms the diagnosis. [2]

• Required specimens: serum, saliva, CSF, and skin biopsy [2]
• Laboratory studies [2]
  • RT-PCR to detect rabies RNA
  • Cell culture to isolate rabies virus
  • Direct fluorescent antibody staining for viral antigen in skin biopsy
  • Indirect fluorescent antibody testing
    • Serum antibodies detected in individuals who are not immunized and did not receive rabies PEP indicate a rabies infection
    • Antibodies in the CSF regardless of the immunization history indicate a rabies infection
  • Virus neutralization test
• Rabies CSF analysis: lymphocytic pleocytosis, ↑ protein, normal or ↑ glucose [5][6]

If a case of rabies is suspected in the US, contact the state health department and CDC to determine if testing is necessary and what specimens are required.

Postmortem diagnosis

• Postmortem brain tissue autopsy
  • Immunofluorescent staining of viral antigen in infected CNS tissue
  • Histopathological findings: Negri bodies (eosinophilic cytoplasmic inclusion bodies typically found in the cerebellum and hippocampus)

For management of individuals with potential rabies exposure, see “Rabies PEP.”

• Symptomatic rabies is almost universally fatal. [2]
• Patients are managed with palliative care (e.g., pain management, sedation).

• Avoiding animal bites is the most effective way to prevent rabies infection. [2]
• Consider rabies PrEP for individuals at increased risk of rabies exposure.
• For potential rabies exposure, consider rabies PEP based on rabies risk assessment.

• Indications: individuals at increased risk of rabies exposure, e.g., [6][7]
  • Occupational exposures (e.g., veterinarians)
  • Recreational exposures (e.g., spelunkers)
  • Travelers to endemic areas
• Immunization schedule: See “Vaccines before travel.”

Rabies PEP is still required for patients exposed to rabies who previously received rabies PrEP. [2]

Recommendations in this article are consistent with the CDC and ACIP guidelines for rabies PEP. [8][9] Consider following the WHO guidelines for rabies PEP in resource-limited settings. [10]

Approach [6]

• Manage bite wounds (e.g., with irrigation, debridement).
• Perform a rabies risk assessment based on the source and nature of exposure.
• Administer rabies PEP if required.
• Follow local protocols for animal observation, testing, and reporting requirements.
• Inform the patient when to return for subsequent rabies vaccinations.

Rabies risk assessment [6][8]

Wild animal bites

• High-risk animals (e.g., bats, raccoons, skunks, foxes, other carnivores) and monkeys
  • Animal is not present: Administer rabies PEP.
  • Animal is present: Contact the local health department for expedited animal rabies testing.
    • Positive: Administer rabies PEP.
    • Negative: No rabies PEP is necessary.
    • If results cannot be obtained expeditiously, initiate rabies PEP and discontinue if negative.
• Low-risk animals (e.g., rodents, lagomorphs): No rabies PEP is necessary.

Any suspicion of a bat bite (e.g., waking up with a bat in the room) warrants the administration of rabies PEP, even if there is no evidence of a bite. [2]

Domestic animal bites

• Dogs, cats, ferrets
  • Animal is not present: Administer rabies PEP.
  • Animal is present: Confine and observe the animal for 10 days.
    • Animal becomes symptomatic
      • Administer rabies PEP.
      • Contact the local health department for expedited animal rabies testing.
      • If animal rabies testing is negative, discontinue rabies PEP.
    • Animal remains asymptomatic: No rabies PEP is necessary.
• Other domestic animals: Consult the local health department.

Rabies PEP regimens [2]

Unvaccinated patients [6][8][9]

• Rabies immune globulin (RIG) [2]
  • Infiltrate as much RIG as feasible into and around the wound.
  • Inject the remaining RIG at a site distant from the site of vaccine administration.
• PLUS inactivated rabies vaccine [2]
  • Administer on days 0, 3, 7, and 14.
  • Immunosuppressed patients: Administer an additional dose on day 28.

Unvaccinated patients require passive immunization (i.e., RIG) and active immunization (i.e., rabies vaccine).

Vaccinated patients [6][7]

An individual is considered vaccinated against rabies if they have previously completed rabies PrEP, rabies PEP, or they have partially completed the rabies vaccination series and have positive rabies antibody titers. [2]

• Inactivated rabies vaccine on days 0 and 3 [2]
• RIG is not required.