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
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
