Rabies virus

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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