Rabies virus

Background

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

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

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

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

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

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

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

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

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