RABIES

MICROBIOLOGY

Rabies is a zoonosis generally transmitted to humans by the bite of a rabid animal and caused by rabies virus—a nonsegmented, negative sense, single-strand RNA virus in the family Rhabdoviridae. Each animal reservoir harbors distinct rabies virus variants.

EPIDEMIOLOGY

Worldwide, canine rabies causes ∼59,000 human deaths each year, most of them affecting rural populations and children in Asia and Africa.

  • Endemic canine rabies has been eliminated in the United States and most other resource-rich countries but persists in bats, raccoons, skunks, and foxes. In 2015, there were 5508 confirmed animal cases of rabies in the United States.
  • Bats (especially silver-haired and tricolored bats) cause most human cases in North America, although there may be no known history of a bat bite or other bat exposure.

PATHOGENESIS

The incubation period can range from a few days to >1 year but is usually 20–90 days. During most of this period, rabies virus is present at or close to the site of the bite.

  • The virus binds to postsynaptic nicotinic acetylcholine receptors and spreads centripetally along peripheral nerves toward the CNS at a rate of up to ∼250 mm/d. Establishment of CNS infection is followed by centrifugal spread along peripheral nerves to other tissues, including salivary glands—hence the excretion of virus in the saliva of rabid animals.
  • The most characteristic pathologic CNS finding is the Negri body—an eosinophilic cytoplasmic inclusion that is composed of rabies virus proteins and viral RNA and is found primarily within Purkinje cells of the cerebellum and in pyramidal neurons of the hippocampus.

CLINICAL MANIFESTATIONS

Rabies usually presents as atypical encephalitis with preservation of consciousness; the disease may be difficult to recognize after the onset of coma. This disease, which usually leads to death despite aggressive therapy, has three phases.

  • Prodrome: Pts have fever, headache, malaise, nausea, vomiting, and anxiety or agitation lasting 2–10 days. Paresthesias, pain, or pruritus near the site of exposure (which has usually healed at this point) is found in 50–80% of cases and strongly suggests rabies.
  • Acute neurologic phase: Pts present with the encephalitic (furious) form of rabies in 80% of cases and with the paralytic form in 20%.
    • Encephalitic form: Pts develop signs and symptoms common to other viral encephalitides (e.g., fever, confusion, hallucinations, combativeness, and seizures) that last 2–10 days. Autonomic dysfunction is common and includes hypersalivation, gooseflesh, cardiac arrhythmia, and/or priapism.
      • A distinguishing feature of rabies is prominent early brainstem dysfunction resulting in hydrophobia and aerophobia (involuntary, painful contraction of the diaphragm and the accessory respiratory, laryngeal, and pharyngeal muscles in response to swallowing liquid or exposure to a draft of air).
      • Hypersalivation and pharyngeal dysfunction produce characteristic foaming at the mouth.
      • Death usually occurs within days of brainstem involvement. With aggressive supportive care, late complications include cardiopulmonary failure, disturbances of water balance (syndrome of inappropriate antidiuretic hormone secretion or diabetes insipidus), and GI hemorrhage.
    • Paralytic form: For unknown reasons, muscle weakness predominates but cardinal features of rabies encephalitis (hyperexcitability, hydrophobia, aerophobia) are lacking. Muscle weakness usually begins in the bitten extremity and proceeds to quadriparesis.
  • Coma and death: Even with aggressive supportive measures, recovery is rare. Death usually occurs within 2 weeks.

DIAGNOSIS

In North America, the diagnosis is often considered relatively late in the clinical course. Rabies should be considered for pts with acute atypical encephalitis or acute flaccid paralysis (including those in whom Guillain-Barré syndrome is suspected).

  • Most routine laboratory tests in rabies are normal or nonspecific; it is important to test for alternative, potentially treatable diagnoses.
  • Negative antemortem rabies-specific laboratory tests never exclude a diagnosis of rabies, and tests may need to be repeated after an interval for diagnostic confirmation.
    • In a previously unimmunized pt, serum neutralizing antibodies to rabies virus are diagnostic, but these antibodies may not be present until late in the disease course. The presence of rabies virus–specific neutralizing antibodies in CSF suggests rabies encephalitis, regardless of immunization status.
    • Reverse-transcription PCR (RT-PCR) can detect virus in fresh saliva samples, CSF, and skin and brain tissues.
    • Direct fluorescent antibody testing is highly sensitive and specific and can be applied to brain tissue or skin biopsy samples from the nape of the neck (where virus is found in cutaneous nerves at the base of hair follicles).

Treatment: Rabies

Management is palliative and supportive. There is no established treatment for rabies.

PREVENTION

Rabies is almost uniformly fatal but is nearly always preventable with appropriate postexposure prophylaxis during the incubation period. Only 15 pts have survived infection with rabies virus, and only one of these pts had not received rabies vaccine before disease onset.

  • An algorithm for rabies postexposure prophylaxis is depicted in Fig. 106-1.
    • Local wound care (e.g., thorough washing, debridement of devitalized tissue) can greatly reduce the risk of rabies.
    • Inactivated rabies vaccine should be given as soon as possible (1 mL IM in the deltoid region), with doses repeated on days 3, 7, and 14 for previously unvaccinated pts; previously vaccinated pts require booster doses only on days 0 and 3.
    • All previously unvaccinated pts should receive human rabies immune globulin (RIG, 20 IU/kg; 40 IU/kg for equine RIG) no later than 7 days after the first vaccine dose. The entire dose should be infiltrated at the site of the bite; if not anatomically feasible, the residual RIG should be given IM at a distant site.
  • Preexposure prophylaxis is occasionally given to persons at high risk (including certain travelers to rabies-endemic areas). The primary vaccine schedule consists of doses on days 0, 7, and 21 or 28.
FIGURE 106-1
hmom20_ch106_f001.png

Algorithm for rabies postexposure prophylaxis. RIG, rabies immune globulin. (From L Corey, in Harrison’s Principles of Internal Medicine, 15th ed. E Braunwald et al [eds]: New York, McGraw-Hill, 2001; adapted with permission.)

Outline

RABIESis the Harrison's Manual of Medicine Word of the day!