Rabies Virus

Rabies virus is a single-stranded, negative-sense RNA virus. This bullet-shaped virus belongs to the family Rhabdoviridae and the genus Lyssavirus. Rabies is a preventable disease most often transmitted to humans through the bite of an infected animal (e.g., bats, raccoons, skunks, and foxes). This life-threatening disease affects the CNS, resulting in severe neurologic manifestations. There are 5 stages of disease in humans: incubation, prodrome, acute neurologic period, coma, and death. The diagnosis is made with antibody, antigen, or viral RNA detection in tissue biopsy, serum, CSF, and saliva. There is no effective treatment for symptomatic disease, so prevention with human rabies immunoglobulin and vaccination is the mainstay of management.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics and Epidemiology

Basic features of rabies virus

  • Taxonomy:
    • Family: Rhabdoviridae
    • Genus: Lyssavirus
  • Midsize:
    • 180 nm long
    • 75 nm wide
  • RNA genome:
    • Single-stranded
    • Linear
    • Negative-sense
  • Structure:
    • Bullet-shaped
    • Helical ribonucleoprotein core
    • Enveloped
    • Glycoprotein spikes on the virus surface
  • Carries RNA-dependent RNA polymerase (RDRP)

Associated disease

Rabies virus causes the disease rabies.

Epidemiology

  • Rabies is present in nearly every country.
    • Developing countries are more affected:
      • Asia
      • Africa
      • Latin America
    • Animal vaccinations in the United States and Europe have largely eliminated rabies in domestic animals. 
  • Approximately 59,000 deaths each year worldwide
  • 2–3 cases per year in the United States
  • Children (boys > girls) are 4 times as likely as adults to get rabies.

Pathogenesis

Reservoir

Mammalian species serve as hosts. In the United States, these may include:

  • Bat
  • Skunk
  • Raccoon
  • Fox
  • Mongoose
  • Coyote
  • Wolf
  • Unvaccinated dogs

Transmission

Human infection is almost always due to a bite by an infected mammal.

  • Most common: saliva of infected animals
  • Rare:
    • Organ transplant
    • Transplacental
    • Inhalation of aerosolized virus

Host risk factors

Susceptibility to lethal infection is related to:

  • Animal species
  • Viral variant
  • Inoculum concentration
  • Location of exposure
    • Head and neck bite versus distal body part
    • Amount of innervation at the bite site
  • Severity of exposure
  • Host immune status

Viral replication cycle

  • Rabies virus binds to receptors on outside host cells → enters host cells by the endosomal transport pathway 
  • ↓ pH in the endosome causes membrane fusion → viral genome reaches the cytosol → viral RNA uncoats in the cytoplasm of infected cells 
  • Genome transcription by a virion-associated RDRP →  viral RNA is translated into viral proteins 
  • Replication occurs with synthesis of positive-stranded RNA templates for the production of negative-stranded RNA.
  • Virions are assembled → virus buds from the cell membrane
Rabies virus life cycle

Rabies virus replication cycle

Image by Lecturio.

Pathophysiology

  • Inoculation → virus has predilection for neural tissue → enters local motor and sensory nerves
  • Travels via peripheral nerves → migrates to the spinal cord → brain
  • Mechanism for encephalitis is unclear.
  • Spreads back through peripheral nerves → disseminates to other parts of the body

Clinical Presentation

5 general stages are recognized in humans: incubation → prodrome → acute neurologic period → coma → death

Incubation

  • Variable from 10 days–2 years, but usually 20–90 days
  • Shorter in children and with bites closer to the CNS

Prodrome

  • Prodromal period lasts 0–10 days.
  • Symptoms are nonspecific
    • General malaise
    • Fever
    • Fatigue
    • Sore throat
    • Cough
    • Dyspnea
    • Nausea and vomiting
    • Headache
    • Pain or paresthesias at the bite site

Acute neurologic period

Acute neurologic period lasts 2–7 days.

Encephalitic form (most common):

  • Hyperactivity and agitation
  • Altered mental status
    • Confusion
    • Hallucinations
  • Pharyngeal muscle spasms
    • Hydrophobia 
    • Aerophobia
    • Choking
    • Coughing
  • Nuchal rigidity
  • Muscle fasciculations and contractions
    • Facial grimacing
    • Back and neck hyperextension
  • Increased deep tendon reflexes
  • Autonomic instability
    • Hypersalivation
    • Sweating
    • Lacrimation
    • Pupil dilation
    • Fever
    • Tachycardia
  • Seizures

Paralytic form:

  • Fever
  • Headache
  • Ascending, flaccid paralysis
  • Muscle fasciculations
  • Absent deep tendon reflexes
  • Bladder dysfunction
Man with Rabies virus

A man with rabies in 1959.

Image: “Rabies patient” by CDC. License: Public Domain

Coma

  • Unresponsive
  • Periods of rapid, irregular breathing
  • Apnea
  • Paralysis

Death

  • Death usually occurs 2–14 days after 1st symptoms appear.
  • Often results from:
    • Respiratory arrest
    • Uncontrolled seizures
    • Cardiac arrhythmias

Diagnosis and Management

Diagnosis

The diagnosis should be suspected in cases of unexplained viral encephalitis with a history of an animal bite. 

Diagnostic methods:

  • Antibody titers
  • PCR to detect viral RNA
  • Isolation of virus (viral culture)
  • Immunofluorescent staining of biopsy specimens for viral antigen

Specimens that can be tested:

  • Saliva
  • CSF
  • Serum
  • Tissue (skin from the nape of the neck or brain)

Management

There is no effective treatment for symptomatic rabies, and few patients survive.

  • Palliative care
  • Life support measures can prolong the clinical course but rarely affect the outcome.

Prevention

Prevention is the mainstay of care.

  • Vaccinate susceptible species (dogs and cats).
  • Preexposure prophylaxis with rabies vaccine is indicated for:
    • Travel to endemic areas
    • Veterinarians
    • Animal handlers
  • Postexposure prophylaxis:
    • Local wound cleaning
    • Human rabies immune globulin (HRIG)
      • Given only once to previously unvaccinated people.
      • Provides immediate antibodies
      • Inject as much as possible at the bite site (infiltrate into the wounds).
      • Remaining volume should be injected IM at a site distant from vaccine administration
    • Rabies vaccine:
      • 1st dose given as soon as possible after exposure. 
      • Additional doses are given on days 3, 7, and 14 after the 1st vaccination.

Differential Diagnosis

  • Bacterial meningitis: acute infection of the meninges. Patients present with headache, fever, nuchal rigidity, and rapid clinical deterioration. A lumbar puncture is performed to make the diagnosis. Unlike with viral meningitis, CSF studies will show a turbid fluid, low glucose, and high WBC with neutrophil predominance. Gram stain and culture will determine the causative bacteria. Treatment includes antibiotics and corticosteroids.
  • Herpes simplex encephalitis: severe CNS infection caused by herpes simplex viruses. Patients develop rapid onset of fever, headache, altered level of consciousness, focal neurologic deficits, and seizures. The diagnosis is confirmed with PCR testing of CSF. MRI may show hyperintense lesions in the temporal lobes. IV acyclovir is the treatment of choice.
  • Tick-borne encephalitis virus: member of the genus Flavivirus transmitted primarily by Ixodes ticks. Most patients infected with with tick-borne encephalitis virus are asymptomatic; however, symptomatic individuals may experience a biphasic illness. After recovering from nonspecific symptoms, patients can develop neurologic manifestations, such as meningitis, encephalitis, or meningoencephalitis. Serology or PCR can confirm the diagnosis. Management is supportive. 
  • West Nile virus: member of the genus Flavivirus transmitted by Culex mosquitoes. Most patients infected with West Nile virus are asymptomatic. A very small proportion of patients develop neuroinvasive disease, which includes meningitis, encephalitis, and acute flaccid paralysis. The diagnosis is confirmed with serum or CSF serology or PCR. Management is supportive. 
  • Saint Louis encephalitis virus: member of the genus Flavivirus transmitted by Culex mosquitoes. Symptomatic individuals may have varied presentations, with flu-like symptoms, aseptic meningitis, encephalitis, or meningoencephalitis. Diagnosis is confirmed with serology. Management is supportive.
  • Equine encephalitis viruses: members of the family Togaviridae. The equine encephalitis viruses are mosquito-borne arboviruses that can cause minor viral illness or encephalitis (in severe cases). Diagnosis is by CSF evaluation, serology, or PCR. Management is supportive.
  • Guillain-Barré syndrome (GBS): acute, rapidly progressive, acquired inflammatory neuropathy that can be triggered by infectious pathogens. Patients develop progressive, symmetric muscle weakness and sensory loss. Unlike rabies, fever is rare in GBS. The diagnosis is clinical. A lumbar puncture will show a normal cell count and elevated protein. Management requires intensive care support, IV immune globulin, and plasma exchange.
  • Botulism: rare, neuroparalytic syndrome caused by a neurotoxin released from Clostridium botulinum. Botulism presents with blurred vision, respiratory failure, and symmetric, descending flaccid paralysis. Unlike rabies, fever is absent. Diagnosis is made on clinical grounds and can be confirmed by the isolation of bacteria or toxins from stool, wound specimens, or food sources. Treatment requires prompt management of respiratory failure, administration of antitoxin, and supportive care for paralysis.
  • Tetanus: bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. Tetanus presents with lockjaw, neck stiffness, opisthotonus, rigid abdomen, and severe, painful muscle spasms. Diagnosis is made on clinical grounds, as it is rarely possible to isolate the infectious agent from the wound. Tetanus is treated with antibiotic therapy and the human tetanus antitoxin.

References:

  1. Baron, S., Rupprecht, C. (1996). Rhabdoviruses: rabies virus. Chapter 61 of Medical microbiology, 4th ed. University of Texas Medical Branch at Galveston.  
  2. Centers for Disease Control: Rabies prevention (1991). Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 40(RR-3):1.
  3. Centers for Disease Control: Compendium of animal rabies control (1995). MMWR 44(RR-2):1.
  4. Centers for Disease Control: Human rabies (1995). MMWR 44:269.
  5. Charlton KM. (1994). The pathogenesis of rabies and other lyssaviral infections: recent studies. Curr Top Microbiol Immunol 187:95.
  6. DeMaria, A., Jr., Brown, C. (2020). Clinical manifestations and diagnosis of rabies. UpToDate. Retrieved May 10, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-rabies
  7. Brown, C.M., DeMaria, A., Jr. (2020). When to use rabies prophylaxis. UpToDate. Retrieved May 16, 2021, from https://www.uptodate.com/contents/when-to-use-rabies-prophylaxis
  8. Jackson, A.C. (2021). Treatment of rabies. UpToDate. Retrieved May 16, 2021, from  https://www.uptodate.com/contents/treatment-of-rabies
  9. Koury, R., Warrington, S.J. (2020). Rabies. [online] StatPearls. Retrieved May 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK448076/
  10. Greenlee, J.E. (2020). Rabies. MSD Manual Professional Version. https://www.msdmanuals.com/professional/neurologic-disorders/brain-infections/rabies
  11. Gompf, S. (2019). Rabies. Emedicine. Retrieved May 10, 2021, from: https://emedicine.medscape.com/article/220967-overview

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