Rabies

September 30, October 5,

2010

“IF A DOG IS MAD THE AUTHORITIES HAVE BROUGHT THE FACT TO THE KNOWLEDGE OF ITS OWNER; IF HE DOES NOT KEEP IT IN, IT BITES A MAN AND CAUSES HIS DEATH, THEN THE OWNER SHALL PAY TWO THIRDS OF A MINA (40 SHEKELS) IN SILVER. IF IT BITES A SLAVE AND CAUSES HIS DEATH HE SHALL PAY FIFTEEN SHEKELS OF SILVER.”

Eshnunna Code (pre 23rd century BC)

Viruses with -ve RNA genomes

Paramyxoviridae

Rhabdoviridae

Orthomyxoviridae

Filoviridae

Bunyaviridae

parainfluenza virus

canine distemper virus

respiratory syncytial virus

rabies virus

vesicular stomatitis virus

influenzaviruses

Ebola virus

Haantan virus

Rhabdoviruses

• Genus Lyssaviruses (neurological)

• Genus Vesiculovirus (epithelial)

• Genus Ephemerovirus

Lyssavirus structureP

P

Genotypes of Lyssavirus

• 1. Classical rabies (genotype 1)

• 2. Lagos bat virus

• 3. Mokola virus

• 4. Duvenhage virus

• 5. European bat virus

• 6. European bat virus

• 7. Pteropus Lyssavirus

Global distribution of rabies

New Zealand

Japan

UK

World wide, EXCEPT

“pteropus lyssavirus” in Australia and UK

• political considerations

Epidemiology of rabies

Species selection and variants of genotype 1 rabies virus

• suggests that each variant circulates mainly in one species

• occasional spillover

• may explain minor differences in susceptibility but virus just as fatal

Differences between variants

• Monoclonal antibody typing

• Sequencing of PCR products

Rabies variants in North America

• Terrestrial– Skunk– Fox - red and arctic– Grey fox– Raccoon– Coyote

• Bat (most of the unexplained human cases in N.America)

distribution of reservoir selected terrestrial rabies in N. America

rabies transmitted by bites……but what if……

Bat-associated rabies virus in Skunks.Leslie MJ, Messenger S, Rohde RE, Smith J, Cheshier R, Hanlon C, Rupprecht CE.Emerg Infect Dis. 2006 Aug;12(8):1274-7

Rabies was undetected in terrestrial wildlife of northern Arizona until 2001, when rabies was diagnosed in 19 rabid skunks in Flagstaff. Laboratory analyses showed causative rabies viruses associated with bats, which indicated cross-species transmission of unprecedented magnitude. Public health infrastructure must be maintained to address emerging zoonotic diseases.

Bat rabies

• In N. America - 700 to 800 encounters per year

• source of most human cases

• 70% of human cases and 75% of cryptic deaths

• vampire bats in Mexico

silver-haired bat(Lasionycteris noctivagans)

Derek Donald

Lasionycteris noctivagans (silver haired bat)

Pipistrellus subflavus (eastern pipstrelle)

Rabies cases in Canada 2008

http://www.inspection.gc.ca/english/anima/disemala/rabrag/statse.shtml#a2009

Was the Rabid ?

The story begins…..

“Las resultas” (Goya)

vampires appear in the form of dogs, wolves or bats

bite turns person into vampire

rabies is zoonotic, animals most likely to be affected by “furious form” are canids and felids. Isosymptomatic

spread by bite

aggressive, violent, libidinous

nocturnal

protective measures - garlic, strong smelling substances, crucifixes, mirrors, water. Vampires grimace and are repulsed by these objects

virus causes lesions in “limbic” areas of CNS (hypothalamus, hippocampus, amygdaloid complex) -> loss of control, insomniahyperesthesia, painful spasms of facial, laryngeal, pharyngeal muscles - precipitated by bright objects, strong smells, water

on exhumation vampires look alive, drool blood, scream when pierced through heart with stake

after death by asphyxia blood remains fluid for some time

burial in cold, wet locations leads to saponification

putrification leads to gas buildup

Symptoms of rabies• Loss of appetite, anxiety, insomnia

• Infection of the limbic system (hypothalamus, hippocampus, amygadala)– Restlessness, wandering,– Hypersensitivity to stimulus– Hydrophobia, muscular spasms of facial,

laryngeal, pharyngeal muscles• Triggered by light, odors, water

– Blood in vomit, inability to swallow saliva– hypersexuality

Pathogenesis: infection and incubation period

infection other(transplants, ingestion)

bites

mucosal exposure

replication at site

No antibody(antibody can prevent further spread - postexposure vaccination)

Incubation period 14-90 days (7 years!)

Pathogenesis: Spread to the brain, clinical signs

infection of neurons

centripetal spread toneurons in DRG or spinal cord, spread to brain

centrifugal spread to sal. glands, skin

clinical signs

Furious (limbicSystem)

Dumb(neocortex)

Virus shedding

2-3 days

death

what causes behavioural changes, paralysis, death?

rabies-infected neurons are negative for apoptotic markers

H&E anti-rab

caspase 3 TUNEL

Jackson et al. 2008, J. Neurovir. 14:368-375

rabies histopathology

• mononuclear infiltration

• perivascular cuffing (lymphocytes and PMN)

• Babes nodules (glial cells)

• Negri bodies

http://www.cdc.gov/rabies/diagnosis.html

Negri Bodies

Negri body ina neuron cell body In the trigeminal ganglion

An electron micrographof a Negri body with budding virus particles

human case

Vaccines

• inactivated virus vaccines

• modified-live (wild-life baits)

• vectored vaccines

rabies vaccines licensed in Canada (2009)

http://active.inspection.gc.ca/scripts/database/vetbio_submit.asp?lang=e&species=11&manufacturer=all

Vaccines for control in wild-life

• Modified live• Vectored (vaccinia or canary-pox virus)

– monitoring (tetracyclin, antibodies)

Prevention, management and control of rabies - Definitions

• Domestic animals – livestock and pets

• Pets – dogs, cats, ferrets (or case by case basis)

• Currently vaccinated – if primary vaccinated >30 days previously or vaccination status current based on duration of vaccine used (3 vs 1)

• Not vaccinated – pet not vaccinated or adult animals only vaccinated once (no boosters)

• Expired vaccination – 2 or more documented vaccinations but currently overdue.

• Home quarantine – physically confined (fence, chain, cage, indoors etc). Contact minimized, can not leave property. Bites of behaviour changes reported immediately.

• Home observation – monitored by owner for signs consistent with rabies.

Compendium of Animal Rabies Prevention and Control,

Vaccine Administration All animal rabies vaccines should be restricted to use by, or under the direct supervision of a veterinarian.

Vaccine Selection In comprehensive rabies-control programs, only vaccineswith a 3-year duration of immunity should be used. This constitutes the most effective method ofincreasing the proportion of immunized dogs and cats in any population. No lab or epi. data to support annual or biannual admin. of 3-year vaccines following initial series.

JAVMA, 2008, 232:1480- 1486

Preexposure Vaccination and Management.

Dogs, cats, and ferrets. All dogs, cats, and ferrets should be vaccinated against rabies at 3 months of age and revaccinated with a single dose of vaccine and placed on an annual or triennial schedule, depending on the type of vaccine used.

• Vaccinated pet (options)

– Immediate revaccination (if within 5 days of exposure). 45 day observation

– Immediate titre check (if within 5 days of exposure). Observation until results obtained

• >0.5IU/ml. 45 day owner observation

• <0.5IU/ml. pet not deemed vaccinated

– Three month quarantine (or if >5 days following exposure

– Euthanasia

Postexposure Management. Any animal potentially exposed to rabies virus by a wild, carnivorous mammal or a bat that is not available for testing should be regarded as having been exposed to rabies.

• Primary vaccinated pet (options)

– Immediate revaccination (if within 5 days of exposure). 45 day observation

– Three month quarantine (or if >5 days following exposure

– Euthanasia

• Non-vaccinated pet (no vaccine or initial vaccine<30 days)

– Immediate euthanasia

– Six month quarantine, vaccinated at end

• “exotic” species (wolf, hybrids etc)

– Euthanize despite vaccination status

Postexposure Management:

Livestock. All species of livestock are susceptible to rabies; cattle and horses are among those most frequently infected. Livestock exposed to a rabid animal and currently vaccinated with a vaccine approved for that species should be revaccinated immediately and observed for 45 days. Unvaccinated livestock should be slaughtered immediately. If the owner is unwilling to have this done, the animal should be kept under close observation for 6 months.

Management of animals that bite humans

• healthy dog, cat, ferret– 10 day observation period– do not vaccinate during observation– report any clinical signs to dist. vet.

• animal showing suspicious signs– report to dist. vet.– euthanize and test

Memo from CFIA, May 2005Where possible biting dogs, cats or ferrets should not be

euthanized but observed for 10 days.1.To avoid needless euthanasia of rabies free animals (from

1999-2003, CFIA tested 6,695 dogs and 5,538 cats. Of these only 7 dogs and 11 cats tested positive (all had displayed abnormal behaviour).

2.High cost for testing animals that are of negligible risk3.Human health consideration - possibility of false

negative test on asymptomatic animals.

Canadian - Health of animals Act (Section 5)

• A person who owns or has the possession, care or control of an animal shall notify the nearest veterinary inspector of the presence of a reportable disease or toxic substance, or any fact indicating its presence, in or around the animal, immediately after the person becomes aware of the presence or fact.

• Immediately after a person who is a veterinarian or who analyzes animal specimens suspects that an animal is affected or contaminated by a reportable disease or toxic substance, the person shall so notify a veterinary inspector.

A suspect case/exposure - What steps to take

• duties as veterinarian– initial assessment and reporting– collection and submission of specimen

• if person exposed (or suspected)– wash wound– notify dist. veterinarian

• if animal exposed– notify dist. vet.– post exposure management– management of animals that bite

Bats

• “in situations in which a bat is physically present and the person(s) cannot exclude the possibility of a bite, postexposure treatment should be considered unless prompt testing of the bat has ruled out rabies infection”.

(CDC)