Rabies virus

Background

Microbiology

• A neurotropic single-stranded, negative-sense RNA virus that causes a zoonotic and universally-fatal encephalitis
• Within the Rhabdoviridae family, the Lyssavirus genus includes multiple serotypes, including the rabies virus (serotype 1) and Australian bat lyssavirus (ABLV) (serotype 7)
  • Other Rhabdoviridae genera include Vesiculovirus (vesicular stomatitis virus), Ephemerovirus (bovine ephemeral fever virus), and Novirhabdovirus (infectious hematopoietic necrosis virus)
• Lyssaviruses are bullet-shaped, with a nucleocapsid enclosed in a lipoprotein envelope with glycoprotein (G protein) spikes
• Five genes:
  • N protein: nucleocapsid protein
  • P protein (or nonstructural (NS) protein): involved in phosphorylation
  • M or M₂ protein: matrix protein
  • G protein: glycoprotein, the primary immunogenic antigen
  • L protein: large RNA-dependent RNA polymerase

Pathophysiology

• The virus enters through a break in the skin, over a mucosal membrane, or through the respiratory tract
• Multiple mechanisms involved in cell attachment, after which it is brought into the cell and escapes from the lysosome into the cytoplasm
• It replicates locally, first, likely in muscle cells initially, then spreads to the nerve that innervates it
• It spreads from peripheral to central via axons, reaching the dorsal root ganglia within 60 to 72 hours
  • Reportedly spreads 0.5 to 1 cm per day
• From the spinal cord, it reaches the CNS and eventually involves almost every neuron
• From the CNS, it spreads back out to the peripheral nerves, including to the oral mucosa, where it replicates in the salivary glands
• Unclear mechanism of damage to the neurons themselves
• Whether the presentation is encephalitic or paralytic depends in large part on the presence of cellular immune response, which favours encephalitic
  • The virus causes apoptosis of CD4+ cells
• Brain histopathology is characterised by Negri bodies in the hippocampal pyramidal cells
  • Otherwise, there's only vascular congestion without evidence of necrosis or other acute damage

Epidemiology

• Worldwide distribution, except Antarctica, New Zealand, Sweden, Norway, Spain, Taiwan, Japan, and some islands
  • An underestimated 55,000 annual deaths worldwide
• Numerous animal reservoirs, including dogs, bats, raccoons, skunks, and foxes
  • No risk with small rodents, since they tend to be killed at the time they're innoculated by the larger animal's mouth
  • In the developed world, wild animals are the major reservoir since domestic dogs are all vaccinated
    • In Ontario, 3.5% of bats have rabies
  • In the developing world, dogs are the major reservoir
• Case reports of transplantation-associated rabies
• The virus doesn't tolerate extremes of pH (<3 or >11), and is killed by UV light, sunlight, desiccation, and numerous chemicles

Clinical Manifestations

• Incubation period ranges from days to more than 19 years, with 75% developing symptoms within 90 days
  • The initial contact is usually a bite but can also be direct contact without history of bite; rarely no exposure remembered
• Prodrome is nonspecific, with fever, headache, malaise, coryza, and GI disturbance
  • May include subtle personality changes or confusion, with parasthesias near the exposure site
  • Myoedema with deep tendon reflexes begins
  • Prodrome lasts for 4 days (2 to 10 days)
• Up to 10 days after the prodrome, the patient develops either encephalitic (furious) rabies or paralytic (dumb) rabies
  • Depends on host immune response
  • Both terminate in coma and death within a few weeks
  • Rare atypical cases may present with sensory or motor deficits, choreiform movements, focal brainstem signs, cranial nerve palsies, myoclonus, and seizures
  • Both forms can also include GI distubance (including bleeding, vomiting, diarrhea, and ileus), cerebral edema, myocarditis, arrhytmias, and heart failure

Encephalitic (furious) rabies

• 80% of cases, lasts 2 to 7 days
• Hydrophobia is a well-known feature
  • Starts as involuntary oropharyngeal or esophageal spasm when drinking water, then develops strong association with water, such that even the sound of water drops can cause agitation
  • Also aerophobia, such as fans or other moving air
• Episodic hyperactivity, seizures, and aerophobia
• Water balance disorders, including SIADH and diabetes insipidus
• Hyperventilation, then periodic ataxic respiration, then apnoea
• Autonomic dysregulation, including mydriasis, anisocoria, piloerection, salivation, sweating, and rarely priapism
• Myocarditis and arrhythmias, including SVT and bradycardia
• Eventually coma and death, usually within 1 to 2 weeks

Paralytic (dumb) rabies

• 20% of cases, lasts 2 to 7 days
• No hydrophobia, hyperactivity, or seizures
• Rather, presents as an ascending paralysis similar to Guillain-Barré syndrome, that is more severe in the bitten limb
• The patient becomes confusion, then comatose, then dies

Diagnosis

• Microscopy
  • Direct fluorescent antibody (DFA) staining of a neck nape full-thickness skin biopsy that contains 10 hair follicles
    • Sensitivity about 50% in first week, increasing over time
    • Current standard test
    • Uses monoclonal antibody to virion or nucleprotein conjugated with FITC
  • Direct rapid immunohistochemistry (DRIT)
  • Formalin-fixed DFA (FFDFA)
  • Histopathology demonstrating Negri bodies
• Molecular testing
  • rtPCR of tissue (e.g. neck skin biopsy) or saliva
• Serology
  • Antibodies may be detectable as early as day 6 of illness, with rapid fluorescent focus inhibition test (RFFIT) for rabies G protein
    • Sensitivity increases to 100% by day 14
    • Serum antibodies seen first, followed by CSF antibodies
• Other investigations
  • CSF may be normal, or have a mild lymphocytosis with elevated protein
  • MRI can be suggestive but not diagnostic

Management

• Supportive care; almost uniformly fatal

Milwaukee protocol

• It exists but isn't helpful

Prevention

Vaccination

• All dogs are vaccinated
• Public health attempts have been made to vaccinate wild animals
• In humans, a vaccine exists
  • Three doses, on days 0, 7, and 21-28
  • Requires serology every 2 to 3 years, with a bosster if titres <0.5 IU/mL
  • Usually reserved for high-risk groups, including vets, lab workers that handle rabies virus, cavers, and international travelers to places with high dog rabies

Post-exposure Prophylaxis

• First aid of the wound
  • Flush the wound with water for 15 minutes
  • Consider iodine or alcohol
  • Give tetanus as appropriate
• The decision to get rabies PEP (RPEP) depends on a number of factors
  • Prevalence of rabies in the community
  • The animal, and whether it can be observed or biopsied
• For domestic dogs, can usually watch the animal for 10 days
• For wild animals, usually need to start within 48 hours while waiting for testing
• For bats specifically, it is recommended to give RPEP when there has been direct contact with the bat, and a scratch or bite cannot be ruled out
• The regimen includes passive rabies immunoglobulin (RIG) as well as vaccine
  • RIG 20 IU/kg IM on day 0 (and not after day 7), if not previously immunized
  • Vaccine on days 0, 3, 7, and 14
    • Another dose at day 28 for immunocompromised patients
    • If previously immunized, give only on days 0 and 3
  • Give at different sites, including RIG near or infiltrated around the wound itself
  • Give the vaccine into the contralateral deltoid
  • If previously vaccinated, no need for RIG but still gets vaccine on day 0 and 3