Dania Jaradat
Tiffany Chang
Group #4 - CASE STUDY AND QUESTIONS: Rabies Virus
An 11-year-old boy was brought to a hospital in California after falling; his bruises were
treated and he was released. The following day he refused to drink water with his
medicine, and he became more anxious. That night he began to act up and hallucinate. He
also was salivating and had difficulty breathing. Two days later, he had a fever of 40.8°C
(105.4ºF) and experienced two episodes of cardiac arrest. Although rabies was suspected,
no remarkable data were obtained from a computed tomographic image of the brain or
cerebrospinal fluid analysis. A skin biopsy from the nape of the neck was negative for
viral antigen on day 3 but was positive for rabies on day 7. The patient’s condition
continued to deteriorate, and he died 11 days later. When the parents were questioned, it
was learned that 6 months earlier, the boy had been bitten on the finger by a dog while on
a trip to India.
1. What clinical features of this case suggested rabies?
In humans, there are five general stages of rabies: incubation period, prodrome, acute
neurologic period, coma, and death (or sometimes, but very rarely, recovery). During the
incubation period, the rabies virus travels slowly through sensory nerves of the peripheral
nervous system towards the central nervous system; because it has not yet infected the central
nervous system, the incubation period generally exhibits no visible clinical symptoms, making
rabies virus easily undetectable. The length of the incubation period generally lasts three to 3 to 8
weeks; but depending on several other factors, can vary greatly from a couple days to over two
years. The prodromal period, which usually lasts from 0 to 10 days, is when the first clinical
symptoms are noted. These are often non-specific symptoms such as those observed with the flu,
including headache, fever, fatigue, malaise, loss of appetite, nausea, vomiting, sore throat,
nonproductive cough, and pain or paresthesia around the site of the wound. Once the virus has
spread to the brain for rapid amplification, the hallmark symptoms or rabies, encephalitis,
ensues. Clinical symptoms during this acute neurological period often manifests themselves in
two different forms: (1) furious rabies, or encephalitic, and (2) dumb rabies, or paralytic. Furious
rabies, experienced by about 80% of the patients, is characterized by anxiety, irritability,
hyperactivity, seizures, convulsions, hallucinations, hydrophobia, aerophobia, and hallucinations.
Dumb rabies, experienced by the other 20% of patients, is characterized by a more subdued
behavior, including paralysis, weakness, and depression. One or both forms may be observed in
the course of a single rabies virus infection. Other clinical symptoms of the acute neurological
period include hyperventilation and hypersalivation. Typically, these symptoms last for 2 to 7
days. Without proper treatment, rabies virus infection progresses and causes the patient’s
condition to deteriorate rapidly, leading to coma, which lasts about 5 to 14 days, and eventually,
to death. Most deaths are due to respiratory failure or cardiac arrest.
Several clinical features of this case study suggest rabies. The most critical piece of
information is found in the patient’s history: six months prior, he had been bitten on the finger by
a dog in India. Rabies virus is most commonly transmitted from mammal to mammal by infected
saliva of a rabid animal bite; while animals such as bats, coyotes, foxes, and raccoons, are all
carriers of rabies virus, dogs are often the most common reservoir and vector species. It affects
people nationwide, but is more commonly found in other areas, such as Latin America, Southeast
Asian, and Africa. In the case study, the boy had visited India, which raises concern due to the
high number of dogs in the area. In India, about 91.5% of animal bites are due to dogs, of which
60% are strays. Because of these high rates, even though the dog that attacked cannot be tested
for rabies, it is safer to administer proper post-exposure prophylaxis to the patient. Additional
symptoms that the patient experienced are parallel to clinical symptoms that appear during the
acute neurological period of rabies virus infection. Specifically, the patient experienced high
fever (40.8°C), anxiety, irritability, difficulty breathing, hypersalivation, hallucinations, and two
episodes of cardiac arrest. Additionally, he refused to drink water, a sign of hydrophobia.
Patients exhibit the classic behavior of hydrophobia due to painful spasms in the throat. Based on
these symptoms presented in the case study and paired with the history of a dog bite, the patient
most likely has a case of “furious” rabies.
2. Why does rabies have such a long incubation period?
The incubation period refers to length of time between initial infection with rabies virus
and the first onset of symptoms. The time course of the incubation period is generally 3 to 8
weeks, but can vary from as short as a couple days to as long as over two years. The longest
reported incubation period of rabies virus is 19 years. It is the most variable period, and often the
longest. Why the incubation is so long has to do with how rabies virus is transmitted and its main
mechanism of infection. Transmission initially begins when the virus from the saliva of an
animal bite enters the tissue. Some viral replication can occur in the muscles near the site of the
wound, but it is very minimal; the majority of replication occurs almost exclusively in neuronal
cells. To reach the central nervous system, however, the virus has to travel from its inoculation
site, into nearby sensory nerves, and slowly move along nerves of the peripheral nervous system
and towards the central nervous system. This stage is known as the incubation period. Because
the virus has a ways to travel before reaching the spinal cord and ascending up to the brain, the
incubation period is relatively long. Upon reaching the brain, the virus replicates exponentially
and causes fatal encephalitis. At this stage, many of the acute neurological symptoms and
behavioral changes of the patient, such as hyperactivity or anxiety, are observed. The virus then
enters the efferent neuronal pathways spreads to many other tissues and organs, such as the heart
and salivary glands.
There are several important factors that determine the length of an incubation period. The
site of the bite wound and its proximity to the central nervous system plays an important role
because it determines the distance the virus will have to travel before reaching the central
nervous system for its main attack. For example, a bite at the leg will have a longer distance of
travel, and therefore a longer incubation period as opposed to a bite at the neck, which is already
close in proximity to the central nervous system. Additionally, the strain of the virus, the severity
of the bite, and the quantity of virus present in the saliva all influence the length of the
incubation period. Other factors include age of the patient and immune status of the host. It is
important to note that the long duration of the incubation period is what makes post-exposure
rabies treatment effective.
3. What treatment should have been given immediately after the dog bite? What
treatment should be given as soon as the diagnosis was suspected?
Post-exposure treatment after rabies virus exposure, generally within 10 days of
initial contact, is highly successful in preventing the progression of rabies virus infection
if administered promptly and correctly. Immediately after the dog bite, post-exposure
prophylaxis should have been administered to prevent infection by the pathogen and
development of the disease. The rabies post-exposure prophylaxis (PEP) regimen includes
three main parts: (1) local treatment of the wound, (2) administration of human rabies
immune globulin, if indicated, and (3) a course of potent and effective rabies
vaccinations. Local treatment of the wound includes flushing and washing the site of
injury for about 15 minutes with soap and water, detergent, or a virucidal agent such as
povidine-iodine. This is very effective in reducing the number of viral particles. The
second part of the PEP regimen involves administration of human rabies immune globulin
(HRIG), which will provide patients immediate antibodies until their body can respond to
the vaccine and actively produce its own. HRIG is given only once on the first day of the
PEP regimen, designated day 0. The dosage given is calculated based on the subject’s
weight and should not exceed 20 units per kilogram body weight. If possible, the full
dosage should be infiltrated around the open wound; any remaining volume should be
administered intramuscularly at a different anatomical site from the vaccine. Since HRIG
may suppress active antibody production, it is critical that the recommended dosage is not
exceeded. For the same reason, if the patient has been previously vaccinated, no HRIG
should be given. The third part of the PEP regimen involves a course of potent and
effective rabies vaccinations. There are currently 3 different vaccinations available:
human diploid cell, purified chick embryo, or rabies vaccine adsorbed. Four 1 mL doses
of the vaccinations are administered over the course of 14 days (days 0, 3, 7, 14), and
given intramuscularly in the deltoid area, for adults, or in the thigh region, for children.
An additional fifth 1 mL dose may be administered on day 28 to immunosuppressed
patients. These vaccinations will allow the patient’s body to actively produce antigens
against the rabies viral antigen, before it is even detected. If the patient has been
previously vaccinated, only 2 doses of booster vaccines are given (days 0 and 3).
The fact that rabies virus has such a long incubation period is what makes postexposure prophylaxis so effective. Early detection and following the treatment protocol is
key to prevention of the viral disease. Once symptoms appear, it is almost always fatal.
Thus, as soon as rabies diagnosis is suspected, the necessary treatments should be given
to prevent further spread of the virus through the central nervous system. A more accurate
diagnosis can include a thorough patient history examination, seeing if there has been a
past case of animal bite – and if so, contact with what type of animal (wild or
domesticated), as well as where the attack occurred, since some parts of the world have a
higher incidence rate of rabies. Laboratory diagnosis includes direct fluorescent antibody
test (dFA) to confirm the presence or absence of rabies antigen in tissue or saliva. Tests
can be performed on samples of: saliva, serum, spinal fluid, hair follicles, and skin
biopsy. dFA results can be confirmed by amplification of a virus isolation and reverse
transcriptase polymerase chain reaction (RT-PCR). It is important to note that, even if the
tests are negative, rabies should not be ruled out immediately. If rabies is at all suspected,
the proper PEP regimen should be followed as a precautionary preventative measure.
Often, by the time laboratory tests are positive, the virus has already spread throughout
the CNS and to other organs, and it is already too late.
4. How do the clinical aspects of rabies differ from those of other neurological viral
diseases?
Rabies virus differs from other neurological viral diseases because it has a completely
different strategy for virus pathogenesis and spread. Rabies virus is primarily transmitted through
animal bites. Because it often kills its hosts, as a means of survival, the virus relies on its
pathogenesis for reinfection in a new host. By the acute neurological period, the virus induces
unmistakable signs of behavior changes (such as hyperactivity, irritability, anxiety); and it is
these behavior changes that are important for further spread of the virus. Unlike many other
viruses, rabies has a 100% mortality rate. It kills its host and has to look for a new one in order to
thrive. Thus, the high replication of rabies in salivary glands of rabid hosts makes the infected
animal a walking “time bomb.”
Rabies also differs from other neurological viral diseases because it has both high
neuroinvasiveness and high neurovirulence. This means that rabies virus is capable of entering
the central nervous system after infection of a peripheral site, as well as causing damage to the
central nervous system, which often leans to paralysis or brain dysfunction. A hallmark symptom
of rabies is acute encephalitis; however, many of the common viruses that cause encephalitis
have low neuroinvasiveness, but high neurovirulence. For example, herpes simplex virus is a
virus of low neuroinvasiveness but high neurovirulence. It normally enters the peripheral
nervous system, and rarely the central nervous system; once it does, however, it is often fatal.
Another example is mumps virus: though it has high neuroinvasiveness like rabies virus, it has
low neurovirulence. Mumps virus can enter the central nervous system from a peripheral site, but
when it does, its symptoms are milder than that of rabies virus. Rabies is unlike most
neurological viral diseases because it has highly neuroinvasive and highly neurovirulent, making
it such a deadly disease.
References:
Centers for Disease Control and Prevention. Rabies.http://www.cdc.gov/rabies/index.html
Hunt, Richard. Virology – Rabies. Microbiology and Immunology On-line. University of South
Carolina School of Medicine. http://pathmicro.med.sc.edu/virol/rabies.htm
Menezes, R. "Rabies in India." Canadian Medical Association Journal 178.5 (2008): 564-66.
Print.
Rupprecht CE. Rhabdoviruses: Rabies Virus. In: Baron S, editor. Medical Microbiology. 4th
edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter
61.Available from: http://www.ncbi.nlm.nih.gov/books/NBK8618/
Wagner, Edward K. Basic Virology. 3rd ed. Massachusetts [etc.: Blackwell Science, 2008. Print.
World Health Organziation. Rabies.
http://www.who.int/mediacentre/factsheets/fs099/en/index.html