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Natural
History
Rabies virus causes an acute encephalitis in all warm-blooded hosts, including
humans, and the outcome is almost always fatal. Although
all species of mammals are susceptible to rabies virus infection, only
a few species are important as reservoirs for the disease. In the United
States, several distinct rabies virus variants have been identified in
terrestrial mammals, including raccoons, skunks, foxes, and coyotes. In
addition to these terrestrial reservoirs, several species of insectivorous
bats are also reservoirs for rabies.
Transmission
Transmission of rabies virus usually begins when infected saliva of a
host is passed to an uninfected animal. Various routes of transmission
have been documented and include contamination of mucous membranes (i.e.,
eyes, nose, mouth), aerosol transmission, and corneal transplantations.
The most common mode of rabies virus transmission is through the bite
and virus-containing saliva of an infected host.
Following
primary infection (see Figure, numbers 1 & 2), the virus enters an
eclipse phase in which it cannot be easily detected within the host. This
phase may last for several days or months. Investigations have shown both
direct entry of virus into peripheral nerves at the site of infection
and indirect entry after viral replication in nonnervous tissue (i.e.,
muscle cells). During the eclipse phase, the host immune defenses may
confer cell-mediated immunity against viral infection because rabies virus
is a good antigen . The uptake of virus into peripheral nerves is important
for progressive infection to occur (see Figure, number 3).
After uptake
into peripheral nerves, rabies virus is transported to the central nervous
system (CNS) via retrograde axoplasmic flow. Typically this occurs via
sensory and motor nerves at the initial site of infection. The incubation
period (see figure, number 4) is the time from exposure to onset of clinical
signs of disease. The incubation period may vary from a few days to several
years, but is typically 1 to 3 months. Dissemination of virus within the
CNS is rapid, and includes early involvement of limbic system neurons
(see Figure, number 5). Active cerebral infection is followed by passive
centrifugal spread of virus to peripheral nerves. The amplification of
infection within the CNS occurs through cycles of viral replication and
cell-to-cell transfer of progeny virus. Centrifugal spread of virus may
lead to the invasion of highly innervated sites of various tissues, including
the salivary glands. During this period of cerebral infection, the classic
behavioral changes associated with rabies develop.
Signs
and symptoms
The first symptoms of rabies may be nonspecific flu-like signs —
malaise, fever, or headache, which may last for days. There may be discomfort
or paresthesia at the site of exposure (bite), progressing within days
to symptoms of cerebral dysfunction, anxiety, confusion, agitation, progressing
to delirium, abnormal behavior, hallucinations, and insomnia. The acute
period of disease typically ends after 2 to 10 days (6). Once clinical
signs of rabies appear, the disease is nearly always fatal, and treatment
is typically supportive. Disease prevention is entirely prophylactic and
includes both passive antibody (immune globulin) and vaccine. Non-lethal
exceptions are extremely rare. To date only six documented cases of human
survival from clinical rabies have been reported and each included a history
of either pre- or postexposure prophylaxis.
Pathology
Pathology of rabies infection is typically defined by encephalitis and
myelitis. Perivascular infiltration with lymphocytes, polymorphonuclear
leukocytes, and plasma cells can occur throughout the entire CNS. Rabies
infection frequently causes cytoplasmic eosinophilic inclusion bodies
(Negri bodies) in neuronal cells, especially pyramidal cells of the hippocampus
and Purkinje cells of the cerebellum. These inclusions have been identified
as areas of active viral replication by the identification of rabies viral
antigen.
Several factors
may affect the outcome of rabies exposure. These include the virus variant,
the dose of virus inoculum, the route and location of exposure,as well
as individual host factors, such as age and host immune defenses.
For
more information about the natural history of rabies, see:
Baer, G. M. (Ed.) (1991). The Natural History of Rabies. Boca Raton,
FL: CRC Press.
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