Rabies is a fatal viral disease transmitted through the bites of infected animals like dogs. It causes inflammation of the brain and is almost always fatal once symptoms appear. The virus is found worldwide except some islands. It is estimated to cause 59,000 human deaths annually, mostly in Africa and Asia. Dogs are the main reservoir with other animals like bats, foxes, and raccoons also transmitting the virus. Transmission occurs through infected saliva entering broken skin or mucous membranes. Prevention focuses on vaccinating animals to control the disease in reservoirs and providing timely post-exposure prophylaxis to people exposed through bites or other contact.

1. PRESENTED BY:
HAFIZ MUHAMMAD MOAVIA
UNIVERSITY OF VETERINARY
AND ANIMAL SCIENCES
LAHORE, PAKISTAN

2. INTRODUCTION
• Rabies is a viral zoonotic disease.
• Responsible for an estimated 59 000 human deaths and over 3.7 million disability-
adjusted life years *(DALYs) lost every year.
• Rabies is the most fatal infection in humans and is almost invariably fatal once clinical
signs occur.
• Most cases occur in Africa and Asia, with approximately 40% of cases in children aged
<15 years.
• Rabies virus is the most important member of the Rhabdoviridae family.
• Rabies virus causes rabies, a viral infection of the central and peripheral nervous
systems that causes encephalitis with or without paralysis.
• No specific antirabies agents are useful, once clinical signs or symptoms develop.
* The overall burden of disease is assessed using the disability-adjusted life year
(DALY), a time-based measure that combines years of life lost due to premature
mortality and years of life lost due to time lived in states of less than full health, or
years of healthy life lost due to disability (YLDs).

3. Sign and
Symptoms

4. EPIDEMIOLOGY
• Geographical distribution:
• Rabies is prevalent throughout the world except in Islands.
• The risk of rabies is highest in countries with hyperendemic canine rabies,
including most of Asia, Africa, and Latin America.
According to World Health Organization (WHO), a country that has no
record of indigenously acquired case of human or animal rabies within
two years period due to surveillance and import regulations can claim
rabies free status.
The countries free from rabies in Asian subcontinent are Bahrain,
Cyprus, Hong Kong, Japan, Malaysia, Maldives, Qatar, Singapore.

5. • The RABV circulates with two epidemiological cycles, which are
interrelated i.e. urban and sylvatic cycle.
• Urbans cycle having mainly pet dogs, cats and in sylvatic cycle wild
mammals like fox, raccoon, jackal, wolf, badger, mongoose and bats,
etc., as vectors/reservoirs, respectively. Both cycles may overlap in
some geographical situations.
• Mainly community and stray dog population maintains the urban
cycle and spill-over to pet dogs creates additional burden to human
with a risk of rabies.

6. Risk factors
• Stray Dog Population
• Urbanization
• Deforestation
• Dog trade (catching, handling, loading, holding, transportation)
• Dog slaughterhouses (un-hygienic practices and unorganized
slaughter houses---dissemination of body parts and by-products to far
off places).

7. Reservoir and source of Rabies
• Dogs are the important reservoir of infection. Other animal reservoirs
include bats, raccoons, skunks, wolves, jackals, foxes, cats, ferrets,
opossums, fowl, etc.
• The virus is excreted in saliva of infected dogs, foxes, wolves, jackals,
vampire bats, raccoons, and skunks. The virus is found in the salivary
gland of these infected animals.
• Infected saliva or infected CNS tissue, including corneal transplants in
humans, are the sources of infection.

8. Transmission of Rabies in humans
The virus is transmitted to humans by following ways:
■ Bite of a rabid dog or other infected animal
■ Contact of saliva with broken skin or with mucous membranes,
exposure to aerosolized secretions from an infected animal(e.g., bat).
■ Corneal transplants: The only documented cases of rabies caused by
human-to-human transmission occurred in eight recipients of
transplanted corneas. Currently, donated corneas are not accepted if
the donor died from encephalitis that may be consistent with rabies.

9. Family and
Genus
• The Rabies virus belongs to Rhabdoviridae
family of RNA viruses.
• The family Rhabdoviridae consists of more
than 185 different viruses isolated from both
plants and animals.
• Currently, animal rhabdoviruses include four
genera:
o Lyssavirus
o Vesiculovirus
oEphemerovirus
oNovirhabdovirus
The rabies virus is the prototypical human
Lyssavirus pathogen.

10. Structure
• Bullet-shaped virus
• It is a negative-sense
• Non-segmented genome
• Single-stranded RNA virus
• The nucleocapsid shows helical
symmetry
• Approximately 100 to 430 nm
long and 45 to 100 nm in
diameter

11. Proteins
• It consists of an outer envelope (E Protein), a lipid-containing bilayer covered with
transmembrane glycoprotein (G protein) spikes. It mediates the attachment of
virus to the acetylcholine receptors of neural tissues.
• Viral matrix proteins (M Protein) are structural proteins linking the viral envelope
with the virus core. They play a crucial role in virus assembly, and interact with the
RNP complex.
• An internal protein core or nucleoprotein(N Protein) encapsidate the nucleic acid
with each molecule of N protein covering nine bases.
• L protein is responsible for the virion-associated RNA polymerase activity and
associated to all activities related to RNA synthesis.
• P protein is responsible for binding L protein to the N protein–RNA template and
inhibits host cell’s interferon production.

12. Replication

13. Pathogenesis
• The virus may enter the peripheral nervous system directly at
the site of bite. In some cases, however, it may replicate in
muscle tissue after entering the host. The virus infects the
sensory neurons and moves rapidly by axonal transport
centripetally to the central nervous system (CNS) for
replication. During its transport within the neurons, it is
protected from the host immune system.
• The virus travels along the axons at a rate of 12–24 mm in a
day to enter the spinal ganglion.
• Its multiplication in the ganglion is indicated by the onset of
pain or paresthesia at the site of the inoculum, which are the
first clinical symptom and a hallmark finding. From here, the
virus spreads quickly, into the CNS, and the spread is marked
by rapidly progressive encephalitis. Thereafter, the virus
spreads to the periphery and salivary glands.
• During the course of infection, encephalitis develops,
associated with the death of neurons and demyelination.
Acidophilic intracytoplasmic neuronal inclusion bodies are
found in infected neurons, which is important for laboratory
diagnosis

15. Stages of Rabies
In general, four stages of rabies are recognized in humans.
• Incubation period
• Prodromal period
• Acute neurologic period
• Coma which subsequently lead to death

16. Incubation Period
• The average period of incubation is 20–90 days and can be as long as
six months.
• During the incubation period;
1) The virus travels from peripheral areas to the CNS.
2) The patients remain asymptomatic during the period.
• Incubation period is influenced by various factors including host
species, virus strain, the amount of inoculum and the site of
introduction of the virus.
• The rabies virus is protected from the immune system during this
period and no antibody response is observed.

17. Prodormal Period
• The virus enters the CNS during the prodromal period.
• The duration of this period is 2–10 days.
• The period is characterized by nonspecific symptoms and sign.
Paresthesia or pain develops at the inoculation site and is
pathognomonic for rabies.
• Other symptoms may include malaise, anorexia, headache, fever,
chills, pharyngitis, nausea, emesis, diarrhea, anxiety, agitation,
insomnia, and depression

18. Acute neurologic period
• This period is associated with objective signs of developing CNS disease.
The duration is 2–7 days. Furthermore, it presents with the following
conditions:
• Furious rabies:
Patients develop agitation, hyperactivity, restlessness, thrashing,
biting, confusion, or hallucinations.
After several hours to days, this becomes episodic and interspersed with
calm, cooperative, lucid periods. Furious episodes last for less than 5
minutes. Episodes may be triggered by visual, auditory, or tactile stimuli, or
they may be spontaneous. Seizures may occur. Autonomic instability is
observed, including fever, tachycardia, hypertension, hyperventilation,
drooling, anisocoria, mydriasis, lacrimation, salivation, perspiration, and
postural hypotension. Other neurologic signs include cranial nerve
involvement with diplopia, facial palsy, and optic neuritis. This phase may
either end in cardiorespiratory arrest or progress to paralysis.

19. Paralytic rabies:
It is also known as dumb rabies or apathetic rabies, because the patient
is relatively quiet compared to a person with the furious form. Paralysis
develops from the outset. Fever, headache, and nuchal rigidity are
prominent. Paralysis is symmetric and may be either generalized or
ascending and may be mistaken for Guillain–Barré syndrome. Calmness
and clarity gradually deteriorates to delirium, stupor, and then coma.

20. Coma
• The patient may go into coma within 10 days of onset; but duration is
variable. Coma leads to respiratory failure within a week of neurologic
symptoms. Hypoventilation and metabolic acidosis predominate.
Acute respiratory distress syndrome is common. Without intensive
supportive care, respiratory depression, arrest, and death occur
shortly after coma.
• A few reports indicate that those patients who survived had pre-
exposure or postexposure prophylaxis supported by most advanced
life-support system.

21. Laboratory
Diagnosis in
Humans

22. Laboratory Diagnosis in Humans
• Specimens:
• Saliva, serum, cerebrospinal fluid (CSF), blood, urine, and skin and brain
biopsy are the frequently used specimens for diagnosis of rabies.
• Microscopy:
Demonstration of Negri bodies by microscopy is the characteristic
histopathological feature of rabies.
Negri bodies are demonstrated in 80% of human cases of rabies. Therefore,
failure to demonstrate Negri bodies in neural tissue does not rule out the
diagnosis of rabies.
Viral antigens can be demonstrated in the corneal smear, skin biopsy collected
from the face or neck, and saliva (antemortem) or in the brain tissue
(postmortem) for diagnosis of rabies

23. • Direct fluorescent antibody technique(DFAT) test using specific monoclonal
antibodies is a specific method to demonstrate rabies antigen in clinical
specimens.
• Isolation of Virus:
• Viruses can be isolated from brain tissue, CSF, saliva, and urine by culture in cell lines
or in animals.
Culture: Isolation of virus in cell lines (WI-38, BHK-21, and CER) is a sensitive method.
demonstration of viral antigen within 2–4 days. The DFA test using monoclonal rabies
antibodies tagged with fluorescein isothiocyanate.
Animal inoculation: Mouse is the animal of choice. CSF, saliva, and urine are
inoculated intracerebrally. After death of the mice or after 28 days of inoculation, the
brain tissues are examined for the presence of Negri bodies by microscopy or for viral
antigen by the DFA test.

24. • Molecular Diagnosis:
• Polymerase chain reaction is being increasingly evaluated for the diagnosis of
rabies. The nucleic acid sequence-based amplification (NASBA) on saliva and
CSF can be used for rapid diagnosis as early as 2 days after symptom onset

25. Laboratory
Diagnosis in
Animals

26. Laboratory Diagnosis in Animals
• In endemic areas, suspect domestic carnivores which have bitten humans should be isolated and
observed for up to 14 days.
• The brains of animals which develop clinical signs should be examined for the presence of virus.
• Rapid laboratory confirmation is essential for the implementation of appropriate treatment of
human patients.
• Non-suppurative encephalitis characterized by perivascular lymphoid cuffing and intracytoplasmic
inclusions (Negri bodies) may be demonstrable histologically.
• The direct fluorescent antibody test (FAT), which provides a rapid and specific diagnosis, may yield
false- negative results with autolysed brain specimens.
• The conjugated antisera usually used for diagnosis are specific for rabies virus (serotype 1).
Rabies virus can be cultured in neuroblastoma cells or in baby hamster kidney cells. Rabies virus,
which is non-cytopathic, can be detected in tissue culture using conjugated antisera.
• Reverse transcriptase polymerase chain reaction (RT- PCR) has been used to detect viral RNA in
brain samples.
• The sensitivity of RT- PCR can be enhanced by combining the technique with ELISA which aids
detection of amplified product

27. Prevention
and Control

28. Prevention and Control
• Pre-exposure prophylaxis:
PrEP is recommended for individuals at higher risk due to occupation, such as dog
handlers, other animal handlers, and veterinarians.
PrEP should be considered in sub-populations living in remote, rabies endemic areas,
where access to PEP is difficult, the dog bite incidence is >5% per year or vampire bat
rabies is known to be present.
For immunologically naive individuals of all age groups WHO recommends the
following PrEP schedules: a 2 sites ID or a 1-site IM vaccine administration on days 0
and 7.
A routine PrEP booster or serology for neutralizing antibody titres is recommended
only if a continued, high risk of rabies exposure remains. Individuals with documented
immunodeficiency should be evaluated on a case-by-case basis and best receive an ID
or IM PrEP schedule as above, plus a third vaccine administration between days 21 to
28. Additionally, in the event of an exposure, a complete PEP course, including RIG, is
recommended.

29. Postexposure Prophylaxis
• Postexposure prophylaxis is started immediately after exposure to
infection. After exposure to possibly infected dog or other rabid
animals, immediate preventive actions are taken up, which consist of
(a) Local treatment
(b) Confirmation whether or not the animal is rabid
(c) Administration of hyperimmune serum
(d) Anti-rabies vaccine

30. • Local treatment:
• This involves prompt cleaning of the wound. The wound should be
immediately scrubbed with soap and water followed by treatment with
quaternary ammonium compounds, tincture, or aqueous solution of iodine or
alcohol.
• Confirmation whether or not the animal is rabid:
• This can be made by clinical observation of suspected dog. If dog is still
healthy 10 days after biting human, rabies is extremely unlikely. Diagnosis can
also be made by demonstration of the Negri bodies in brain tissues at autopsy
or viral antigens in the brain tissue or saliva.

31. • Administration of hyperimmune serum:
• RIG provides passive immunization and is administered only once, as soon as
possible after the initiation of PEP and not beyond day 7 after the first dose of
vaccine. It is carried out by administering purified equine rabies immune globulin
(ERIG) and human rabies immune globulin (HRIG).
• WHO recommends the following:
• The maximum dose is 20 IU (HRIG) and 40 IU (ERIG) per kg body weight.
• Infiltrate as much as possible into the wound; the remainder of the calculated dose
of RIG does not need to be injected IM at a distance from the wound.
• Antirabies vaccine:
• Rabies is the only disease where postexposure vaccination is employed extensively
and successfully. This is due to long incubation period of the disease. The chances of
preventing the rabies are more when vaccination is given to humans as early as
possible after exposure.

32. WHO Rabies Exposure Categories
• Category I touching or feeding animals, animal licks on intact skin (no
exposure)
• Category II nibbling of uncovered skin, minor scratches or abrasions
without bleeding (exposure)
• Category III single or multiple transdermal bites or scratches,
contamination of mucous membrane or broken skin with saliva from
animal licks, exposures due to direct contact with bats (severe
exposure).

33. PEP Recommendations By Category Of
Exposure

35. How different countries have been able to
control rabies successfully
America have reduced canine rabies by over 95% in humans and 98% in
dogs. Australia and UK have also been able to eradicate canine rabies
through:
• Dog vaccination campaigns
• Raising public awareness
• Widespread availability of post exposure prophylaxis (PEP).
• Strict continuous monitoring.
• Quarantine of imported animals.
• Regulations to avoid the entrance of virus particularly with the import
or introduction of infected animals.

36. Rabies in Pakistan
• In 2010, more than 97 000 recorded cases of dog bites were reported by
basic health units alone. Those managed by secondary and tertiary care
facilities, private practitioners and spiritual healers and hakims are not
recorded.
• Research has revealed that most of the population are either unaware of
the risk of rabies when bitten by rabid dogs, or do not seek the right
treatment for its prevention.
• Other weaknesses in the control of rabies in Pakistan include:
• Lack of a surveillance system
• Limited access to up-to-date rabies vaccines and immunoglobulin
• Inadequate resources and political support
• Weak collaboration between different government departments and sectors
including the health authorities, livestock and veterinary science authorities and local
government.

37. WHO response to rabies in Pakistan
The main features of WHO's strategy for rabies control are:
• Mass awareness on rabies transmission, prevention and self-protection using cost-effective methods such as
local government and community communication structures
• Establishment of rabies treatment centres at each district headquarters hospital where health-care
providers will be trained on management and treatment of dog bites with anti-rabies vaccine
• Ensuring the most cost-effective and efficacious anti-rabies vaccines in designated rabies treatment centres
in all districts
• Enactment and enforcement of laws relating to vaccination of pet animals, such as dogs and cats, in order
to decrease rabies incidence among them
• Creation of a mechanism to decrease the stray dog population in districts through the use of modern
methods such as bait vaccination and dog elimination.
• Development of a surveillance system to monitor dog bites, dog rabies and human rabies through the use of
the existing death reporting system under local government structures
• Close collaboration between the three government departments involved in the control of rabies
• Research on animal rabies and the development of animal and human rabies vaccines by the university of
veterinary sciences in lahore.