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„Approved”
on methodical conference
department of infectious diseases and epidemiology
„____” ____________ 200 р.
Protocol № _____
Chief of Dept. __________ V.D.Moskaliuk
METHODOLOGICAL INSTRUCTIONS
to a fifth year student of the Faculty of Medicine
on independent preparation for practical training
Topic: RABIES
Subject:
Major:
Educational degree and qualification degree:
Year of study:
Hours:
Assistant professor
Infectious Diseases
Medicine
Specialist
5
2
Sydorchuk A.S.
Topic: RABIES
1. Lesson duration: 2 hours
2. Aims of the lesson:
3.1. Students are to know:
 Etiology and epidemiology of a rabies;
 Pathogenesis and pathological anatomy;
 Classification of a rabies;
 The clinical characteristic of different kinds of a rabies;
 Laboratory methods of examination at rabies;
 Complications, which are observed at a rabies;
 Differential diagnostics of a rabies;
 Medical tactics;
 Preventive and antiepidemic measures in the locus.
3.2. Students are to be able:
• to question a patient in order for obtaining of information on disease history and
epidemiologic anamnesis;
• to perform clinical examination of a patient;
• to formulate and to substantiate the diagnosis of rabies;
• to prepare a plan of additional patient examination;
• to evaluate results of laboratory examination;
• to make differential diagnosis to distinguish between similar diseases;
• to prescribe adequate pathogen and etiotropic treatment.
3.3. Students are to acquire the following skills:
 to conduct clinical examination of a rabies patient;
 to formulate and substantiate a clinical diagnosis;
 to prepare a plan of paraclinic patient examination;
 to evaluate results of paraclinic patient examination;
 to organize hospitalization and treatment of a rabies patient;
 to plan and organize prophylactic measures against rabies.
4. Advice to the student:
Rabies (Latin: rabies, "madness, rage, fury" also "hydrophobia") is a viral
zoonotic neuroinvasive disease that causes acute encephalitis (inflammation of the
brain) in mammals. In non-vaccinated humans, rabies is almost invariably fatal after
neurological symptoms have developed, but prompt post-exposure vaccination may
prevent the virus from progressing. There are only six known cases of a person
surviving symptomatic rabies, and only one known case of survival in which the
patient received no rabies-specific treatment either before or after illness onset.
The virus is a Lyssavirus. This genus of RNA viruses also includes the Aravan
virus, Australian bat lyssavirus, Duvenhage virus, European bat lyssavirus 1, European
bat lyssavirus 2, Irkut virus, Khujand virus, Lagos bat virus, Mokola virus and West
Caucasian bat virus. Lyssaviruses have helical symmetry, so their infectious particles
are approximately cylindrical in shape. This is typical of plant-infecting viruses;
human-infecting viruses more commonly have cubic symmetry and take shapes
approximating regular polyhedra. Negri bodies in the infected neurons are
pathognomonic.
The virus has a bullet-like shape with a length of about 180 nm and a crosssectional diameter of about 75 nm. One end is rounded or conical and the other end is
planar or concave. The lipoprotein envelope carries knob-like spikes composed of
Glycoprotein G. Spikes do not cover the planar end of the virion (virus particle).
Beneath the envelope is the membrane or matrix (M) protein layer which may be
invaginated at the planar end. The core of the virion consists of helically arranged
ribonucleoprotein. The genome is unsegmented linear antisense RNA. Also present in
the nucleocapsid are RNA dependent RNA transcriptase and some structural proteins.
The differential diagnosis in a case of suspected human rabies may initially
include any cause of encephalitis, particularly infection with viruses such as
herpesviruses, enteroviruses, and arboviruses (e.g., West Nile virus). The most
important viruses to rule out are herpes simplex virus type 1, varicella-zoster virus, and
(less commonly) enteroviruses, including coxsackieviruses, echoviruses, polioviruses,
and human enteroviruses 68 to 71. A specific diagnosis may be made by a variety of
diagnostic techniques, including polymerase chain reaction (PCR) testing of
cerebrospinal fluid, viral culture, and serology. In addition, consideration should be
given to the local epidemiology of encephalitis caused by arboviruses belonging to
several taxonomic groups, including eastern and western equine encephalitis viruses,
St. Louis encephalitis virus, Powassan virus, the California encephalitis virus
serogroup, and La Crosse virus.
New causes of viral encephalitis are also possible, as was evidenced by the
recent outbreak in Malaysia of some 300 cases of encephalitis (mortality rate, 40%)
caused by Nipah virus, a newly recognized paramyxovirus. Similarly, well-known
viruses may be introduced into new locations, as is illustrated by the recent outbreak of
encephalitis due to West Nile virus in the eastern United States.[3] Epidemiologic
factors (e.g., season, geographic location, and the patient’s age, travel history, and
possible exposure to animal bites, rodents, and ticks) may help direct the diagnostic
workup.
Cheaper rabies diagnosis will be possible for low-income settings according to
research reported on the Science and Development Network website in 2008. Accurate
rabies diagnosis can be done ten times cheaper, according to researchers from the
Farcha Veterinary and Livestock Research Laboratory and the Support International
Health Centre in N'Djamena, Chad. The scientists evaluated a method using light
microscopy, cheaper than the standard tests, and say this could provide better rabies
control across Africa.
Any mammal may become infected with the rabies virus and develop symptoms,
including humans. Most animals can be infected by the virus and can transmit the
disease to humans. Infected bats, monkeys, raccoons, foxes, skunks, cattle, wolves,
dogs or cats provide the greatest risk to humans. Rabies may also spread through
exposure to infected domestic farm animals, groundhogs, weasels and other wild
carnivores. Rodents (mice, squirrels etc) are seldom infected.
The virus is usually present in the nerves and saliva of a symptomatic rabid
animal. The route of infection is usually, but not necessarily, by a bite. In many cases
the infected animal is exceptionally aggressive, may attack without provocation, and
exhibits otherwise uncharacteristic behaviour. Transmission may also occur via an
aerosol through mucous membranes; transmission in this form may have happened in
people exploring caves populated by rabid bats.
Transmission between humans is extremely rare, although it can happen through
transplant surgery (see below for recent cases), or, even more rarely, through bites,
kisses or sexual relations.
After a typical human infection by bite, the virus enters the peripheral nervous
system. It then travels along the nerves towards the central nervous system. During this
phase, the virus cannot be easily detected within the host, and vaccination may still
confer cell-mediated immunity to prevent symptomatic rabies. Once the virus reaches
the brain, it rapidly causes encephalitis. This is called the "prodromal" phase. At this
time, treatment is useless. Then symptoms appear. Rabies may also inflame the spinal
cord producing myelitis.
The period between infection and the first flu-like symptoms is normally two to
twelve weeks, but can be as long as two years. Soon after, the symptoms expand to
slight or partial paralysis, cerebral dysfunction, anxiety, insomnia, confusion, agitation,
abnormal behavior, paranoia, terror, hallucinations, progressing to delirium. The
production of large quantities of saliva and tears coupled with an inability to speak or
swallow are typical during the later stages of the disease; this can result in
"hydrophobia", where the victim has difficulty swallowing because the throat and jaw
become slowly paralyzed, shows panic when presented with liquids to drink, and
cannot quench his or her thirst. The disease itself was also once commonly known as
hydrophobia, from this characteristic symptom. The patient "foams at the mouth"
because they cannot swallow their own saliva for days and it gathers in the mouth until
it overflows.
Death almost invariably results two to ten days after the first symptoms; the few
humans who are known to have survived the disease were all left with severe brain
damage, with the recent exception of Jeanna Giese (see below). It is neurotropic in
nature.
Rabies can be prevented by vaccination, both in humans and other animals.
Virtually every infection with rabies resulted in death, until Louis Pasteur and Emile
Roux developed the first rabies vaccination in 1885. This vaccine was first used on a
human on July 6, 1885 – nine-year old boy Joseph Meister (1876–1940) had been
mauled by a rabid dog.
Their vaccine consisted of a sample of the virus harvested from infected (and
necessarily dead) rabbits, which was weakened by allowing it to dry for 5 to 10 days.
Similar nerve tissue-derived vaccines are still used now in some countries, and while
they are much cheaper than modern cell culture vaccines, they are not as effective and
carry a certain risk of neurological complications.
The human diploid cell rabies vaccine (H.D.C.V.) was started in 1967. Human
diploid cell rabies vaccines are made using the attenuated Pitman-Moore L503 strain of
the virus. Human diploid cell rabies vaccines have been given to more than 1.5 million
humans as of 2006. Newer and less expensive purified chicken embryo cell vaccine,
and purified Vero cell rabies vaccine are now available. The purified Vero cell rabies
vaccine uses the attenuated Wistar strain of the rabies virus, and uses the Vero cell line
as its host.
Some recent works have shown that during lethal rabies infection the bloodbrain barrier (BBB) does not allow anti-viral immune cells to enter the brain, the
primary site of rabies virus replication.[7] This aspect contributes to the pathogenicity of
the virus and artificially increasing BBB permeability promotes viral clearance.
Opening the BBB during rabies infection has been suggested as a possible novel
approach to treat the disease.
Post-exposure prophylaxis
Treatment after exposure, known as post-exposure prophylaxis or "P.E.P.", is highly
successful preventing the disease if administered promptly, within six days after
infection and consists of over a 28 day period. Thoroughly washing the wound as soon
as possible with soap and water for approximately five minutes is very effective at
reducing the number of viral particles. "If available, a virucidal antiseptic such as
povidone-iodine, iodine tincture, aqueous iodine solution or alcohol (ethanol) should
be applied after washing." Exposed mucous membranes such as eyes, nose or mouth
should be flushed well with water. In the United States, patients receive one dose of
immunoglobulin and five doses of rabies vaccine over a twenty-eight day period. Onehalf the dose of immunoglobulin is injected in the region of the bite, if possible, with
the remainder injected intramuscularly away from the bite. This is much less painful
compared with administering immunoglobulin through the abdominal wall with a large
needle, as was done in the past. The first dose of rabies vaccine is given as soon as
possible after exposure, with additional doses on days three, seven, fourteen, and
twenty-eight after the first. Patients that have previously received pre-exposure
vaccination do not receive the immunoglobulin, only the post-exposure vaccinations on
day 0 and 3. Since the widespread vaccination of domestic dogs and cats and the
development of effective human vaccines and immunoglobulin treatments, the number
of recorded deaths in the U.S. from rabies has dropped from one hundred or more
annually in the early twentieth century, to 1–2 per year, mostly caused by bat bites,
which may go unnoticed by the victim and hence untreated.
P.E.P. is effective in treating rabies because the virus must travel from the site of
infection through the peripheral nervous system (nerves in the body) before infecting
the central nervous system (brain and spinal cord) and glands to cause lethal damage.
This travel along the nerves is usually slow enough that vaccine and immunoglobulin
can be administered to protect the brain and glands from infection. The amount of time
this travel requires is dependent on how far the infected area is from the brain: if the
victim is bitten in the face, for example, the time between initial infection and infection
of the brain is very short and P.E.P. may not be successful.
Pre-exposure prophylaxis
Currently pre-exposure immunization has been used on domesticated and normal nonhuman populations. In many jurisdictions, domestic dogs, cats, and ferrets are required
to be vaccinated. A pre-exposure vaccination is also available for humans, most
commonly given to veterinarians and those traveling to regions where the disease is
common, such as India. Most tourists do not need such a vaccination, just those doing
substantial non-urban activities. However, should a vaccinated human be bitten by a
carrier, failure to receive subsequent post-exposure treatment could be fatal, although
post-exposure treatment for a vaccinated human is far less extensive than that which
would normally be required by one with no pre-exposure vaccination.
In 1984 researchers at the Wistar Institute developed a recombinant vaccine called VRG by inserting the glycoprotein gene from rabies into a vaccinia virus. The V-RG
vaccine has since been commercialised by Merial under the trademark Raboral. It is
harmless to humans and has been shown to be safe for various species of animals that
might accidentally encounter it in the wild, including birds (gulls, hawks, and owls).
V-RG has been successfully used in the field in Belgium, France, and the United States
to prevent outbreaks of rabies in wildlife. The virus is stable under relatively high
temperatures and can be delivered orally, making mass vaccination of wildlife possible
by putting it in tasty baits. The plan for immunization of normal populations involves
dropping bait containing food wrapped around a small dose of the live virus. The bait
would be dropped by helicopter concentrating on areas that have not been infected yet.
Just such a strategy of oral immunization of foxes in Europe has already achieved
substantial reductions in the incidence of human rabies. A strategy of vaccinating
"neighborhood dogs" in Jaipur, India, (combined with a sterilization program) has also
resulted in a large reduction in the number of human cases.
5. Control questions:
1. Give the characteristic of the originator of rabies.
2. Who is a source of an infection contamination at rabies?
3. Name possible mechanisms and paths of transfer of a rabies.
4. Name the basic phases of a pathogeny of rabies.
5. Clinical forms of rabies and their feature.
6. Name possible complications of rabies
7. With what diseases it is necessary to differentiate rabies?
8. List the basic criteria for an establishment of the diagnosis: " rabies ".
9. What principles of therapy of rabies
10. Pathogenetic treatment of rabies.
6. REFERENCES.
А. Basic:
Infectious disiseases /Edited by: prof. E. Nikitin, prof. M. Andreychyn.-Ternopil
«Ukrmedknyga», 2004.-364 p.
Б. Adding:
1. The Merck Manual of Diagnosis and Therapy.-Merck Sharp, 1987.-2696 p.
2. Reese R.E. A Practical Approach to Infectious Diseases-Boston-Toronto: Little,
Brown&Company, 1986.-782 p.
3. Ellner P.D., Neu H.C. Understanding Infectious Diseases – Mosby Year Book,
1992.- 343 p.