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Current Issues in RabiesMira J. Leslie, D.V.M., M.P.H.

April 4, 2007

Rabies

• Among the oldestinfectious diseaseknown.

• MOST FATALdisease known

• Prevention costs:health care, animalcontrol, public health,laboratory….

Centuries of Fear

• Rabhas –Sanskrit “todo violence” 30 centBC

• Illiad- Hector is“mad dog”

• Egyptian dog Sirius-furious dog

• Celsius, Rome, 1st

cent. AD humanrabies

Rabies virus• Rhabdoviridae• Bullet shaped• 1 of 7+ Lyssavirus

– Classic Rabies– Lagos bat virus– Mokala– Duvenhage– EBLV1 , EBLV2– Australian bat virus

• Encodes 5 proteins• enveloped

• Very few countries are rabies-free. (Hawaii, Australia, U.K.)• Surveillance for rabies is passive and variable• Animal reservoirs vary from country to country.

Encephalitis Caused by a Lyssavirus in Fruit Bats inAustralia

Graeme C. Fraser,* Peter T. Hooper,† Ross A. Lunt,† Allan R.Gould,† Laurence J. Gleeson,† Alex D. Hyatt,† Gail M. Russell,† and

Jaqueline A. Kattenbelt†EID, Volume 2, No 4, Oct-Dec 1996

Characterization of a novel lyssavirus isolated fromPteropid bats in Australia.Gould AR, Hyatt AD, Lunt R, Kattenbelt JA, Hengstberger S,Blacksell SD.Virus Res 1998;54:165-87

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Rabies: background

• Rabies is a viral disease of the central nervoussystem.

• All mammals including humans can beinfected.

• Rabies is transmitted when infective saliva isinoculated under skin or into a mucousmembrane.

• Rabies is fatal once signs develop.

Virus infects and movesretrograde in nerve tissue,not blood.

Rabies infection

• Long Incubation period: usually 3-12 weeks– Dogs: 2weeks-6m– Humans: 2 weeks- 6 years– Wildlife: unknown

• Contagious period (viral shedding in saliva)– Dogs: 1-10 days before death– Humans: ?– Wildlife: ?

Signs of rabies in animals

Abnormal Behavior :• Nocturnal animals acting sick or

active during daylight hours.• Staggering, trembling, weakness,

paralysis, agitation, confusion,hypersalivation, unprovokedaggression, abnormal vocalization,glazed eyes….

• **Grounded bats.• Variable symptoms

Rabies and Public Health• PH (federal, state, local) is involved in every

aspect of rabies

– Guidelines for control and prevention-animals/humans– Managing animal and human exposures– Laboratory testing– Vaccine supply– Surveillance, epidemiology, …– Animal control- may be health or law enforcement– Provide expert consultation to medical and veterinary

community– Investigation of animal and human cases– Media and public education

• 1955- present: Confirmed Rabid animals– wildlife domesticated

• In the U.S., wildlife reservoirs maintain rabies andinfection is transmitted from wildlife to other species.

What happened to reduce dog rabiesin 1950-60?

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Rabies in animals and in humans is anationally notifiable condition

• All cases are tested by Public health labs andaffiliates (some universities)

• Reporting system: clinician (vet, medical) tolocal ph state ph CDC

• Complete investigations (to find exposed peopleand animals) are done on every case.

Skunk

Raccoon

Coyote

Skunk

Fox

Skunk

Fox

Fox

Terrestrial and non-terrestrial rabies reservoirs

**There have been majorchanges in this data in thepast 3 decades

1980:translocationby huntersstartedepizootic

Raccoons and Rabies

• Raccoons efficientlytransmit rabies to:skunks, beaver, fox,groundhogs, cats,dogs, goats, deer,horses, pigs, sheep,cattle, rabbits, …

and humans (more later)

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Skunks and Rabies

• Skunks transmitrabies to :badgers, raccoons,other wildanimals, cats,dogs, humans,cattle, horses, …

Skunk

Raccoon

Coyote

Skunk

Fox

Skunk

Fox

Fox

3 different variants

What accounts for this?

Foxes transmit rabies tocoyotes, bobcat, dogs,horses….llamas, etc

Bats and Rabies• > 1300 rabid bats reported

in US during 2004 (>1400in 2005)

• Widespread distribution• Many species affected• Most bats are healthy- not

rabid• No ‘carrier’ state• Predominant cause of

human infections in US.

Bats with rabies

• Appear injured• Found flapping or dead on ground• Flying during the day• When in urban area, often expose

human and/ or pets– Found in pets mouth– Child finds bat

[269 in 2005]

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Walla, Walla: Sept. 2002

CATS SHOULDBE

VACCINATED![N=76 in 2005]

Rabid puppy: Tucson 2002

• 3-4 month old stray• Given to Humane

Society 3/11• Animal Rescue 3/17• PETsMART 3/22 &

3/24• Euthanized March 29• Rabies test April 2

Rabid Puppy: Follow up• Count back 14 days from

death.• Identify all human and animal

exposures.• Press release, hotline, …• Emergency room notification.• 105 human exposures, 1

unvaccinated animal contactCost of PEP: $250,000?

Rabid puppy• This pup was

vaccinated 2weeksbefore it became ill:what happened?

Incubation period = weeksContagious (shedding)period = days

March April

RabiesExposure

Symptomatic

Vaccination at Humane society & Rescue

Euth/testPetsmart

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Immunology

• A puppy receiving an initial rabies vaccinewill take about 28 days to developimmunity. Subsequent vaccines are“boosters”.

• After being exposed to a rabid animal a petshould have an immediate booster rabiesvaccine (to mount optimal virus neutralizingantibody) .

Pets or feral and stray animals may beexposed to a wild animal

• Test wild animal ifexposure is seen andanimal is available.

Cattle are usually infected by rabid skunks or raccoons,bats, foxes.

DeriengueImported cases of Bovine Paralytic Rabies transmitted by vampire bats in Central America

ARIZONA

MEXICO

Rupprecht C and Gibbons R. N Engl J Med 2004;351:2626-2635

Rabies surveillance is mostly passive and notstandardized among states or counties. Datais not comparable.

Skunk

Raccoon

Coyote

Skunk

Fox

Skunk

Fox

Fox

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Rabies: Evolving Epidemiology

Human factors:1. Importation of foreign

dogs, exotic animals,livestock

2. Interstate movement ofrabies reservoirs

3. Better diagnostics4. Improved surveillance of

wildlife5. Canine vaccination

Animal factors1. Evolutionary adaptation

of virus in new hosts2. Population density3. Susceptibility4. Reservoir range

Translocation of Coyote Rabies -- Florida,1994

– November- December 1994. Rabies was diagnosed infive dogs from two associated kennels in Florida.

– The virus recovered from the five dogs was identified asa variant not previously found in Florida but endemic incoyotes (Canis latrans) in south Texas.

– The source of infection was a group of coyotes that weremoved from Texas to Florida for hunting in a 320 acrefenced foxpen for sport.

MMWR August 11, 1995 / 44(31);580-581,587

Rabies diagnostic tests:

• Direct Fluorescent antibody• Monoclonal antibody test• RT-PCR• EM• Histopathology• IHC•Virus isolation in cell culture•Serology- VNA

Rabies Testing: Direct Fluorescent antibody•DFA: Gold standard diagnostic- veryreliable test. [Only performed at PublicHealth and few university labs]

•Cross sections of fresh brainstem,hippocampus, cerebellum.

Monoclonal antibody and PCR toidentify rabies virus variant.

Rabies Transmission inWashington

Other wildlife and pets

Rabies in WA

• In 2006: 15 rabid / 244tested bats.

• Multiple human andpet exposures

• 5-10% of tested batsare rabid.

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Rabies testing in WA

• WA Public Health Lab: Testinglimited to human exposures- nosurveillance testing done.

• 300-500 animals tested annually• ~50%Domestic/ 50% wild• 98% of positive in WA are bats• 92% of positive nationwide are

wildlife.

Rabies virus variant identificationavailable on cases in unusualspecies and humans.

Spit Happens

•History: Veterinarianexamined, sedated andeuthanized a llama that wasexhibiting abnormalbehavior.Brain tissue sent to veterinarydiagnostic lab.

• Laboratory confirmedrabies.

Site visit to small ranch;5 llamas; 2 have wounds.

Investigation

• Another llama fromsame pen died 2weeks earlier ofundiagnosed acuteillness.

• Exhume for testing.

Investigation• Brain tissue from

exhumed llama testspositive for rabies

One week later:

Wounded llama dies.

Rabies Confirmed.

Summary: 30 days later.Three llamas remained healthy

Three llamas died of fox variant of rabiesOne llama was euthanized due to wound/exposure

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Three rabid llamas in 30 days

• Unusual for rabies to affect group of animals• Llama to llama transmission? Not likely.• What happened?

– River/Wildlife corridor adjoining ranch– Probable single attack by rabid fox on the three male

llamas sharing one pen;– Variable incubation according to amount of viral

inoculum and proximity to nerve–all died within onemonth.

Rabies Vaccines- Animals

• Domestic: parenteral vaccines fordog, cat, ferret, horse, cattle,sheep (see Compendium).

• Wild: Oral recombinant DNAbait vaccine for raccoon, coyote,fox (not used in WA)

• Exotic/wild: No licensed vaccinefor bats, monkeys, llamas, wolf-hybrid…(off- label use byveterinarians)

Citizen finds sick or deadbat or wild carnivore; callsanimal control agency

Animal control picks up animaland submits brain tissue topublic health laboratory.

Rabies virus not detected

Results provided to state and local public health agencies andthe submitter (animal control, veterinarian)

Rabies virus detected

Potential human exposure to rabies

Yes

No

Local, state and nationalrabies databases updated

Veterinarian suspects rabies in a domesticanimal; animal is euthanized or dies; requestspublic health laboratory rabies test

No furtherfollow-up

Public health calls citizen to assessany potential human exposure(s).

Animal control evaluates andregulates management of petanimal exposure(s).

Example of a rabies surveillance and control system

Public health laboratoryperforms rabies test

Refer to healthcare provider

Human Rabies

• Worldwide,rabies causes anestimated30,000-70,000human deathsannually– India, China,…

• “… the patient can neither stand nor lie down;like a madman he flings himself hither andtither, tears his flesh with his hands, and feelsintolerable thirst. This is the most distressingsymptom for he so shrinks from water and allliquids that he would rather die than drink or bebrought near to water; it is then that they biteother persons, foam at the mouth, their eyeslook twisted, and finally they are exhaustedand painfully breath their last.”– Girolamo Francocastro, 16th century

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Human Rabies, U.S. 1980- 2006

N=59

0

1

2

3

4

5

6

7

8

9

80 82 84 86 88 90 92 94 96 98 20 200220042006

Transplant

Raccoon

Bat

ForeignDog

WA cases

Rupprecht C and Gibbons R. N Engl J Med 2004;351:2626-2635

Temporal Trends in the Diagnosis of Rabies in the United States, 1944 to 2002

Rupprecht C and Gibbons R. N Engl J Med 2004;351:2626-2635

Human Rabies

• California• 66 year old male• Hospitalized -chest pain, 2

wk mild headache,drowsy…5d arm pain, 1dhand weakness.

• Steady neuro decline• Died seven days after

hospitalization.

Human Rabies, CA

• Exposure: Bat bite onright index fingerwhile in bed 5 weeksearlier.

• Threw bat out window• Washed wound• Did not seek medical

care or consult publichealth despite advise.

Human Rabies, CA

• Due to bat bite history,rabies diagnosis wasimmediately considered.

• Aggressive Treatment:Vaccine, IG, anti-virals,…

• All treatments failed.

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Case #2

• 10 year old child : died Sept. 27,2005 (post hurricane) Mississippi• No history of sick pets, no animal bite• Bats seen in and around home• Post mortem history; one bat in bedroom

released outdoors by the child• Epidemiology of rabies in Mississippi: bats

are reservoir.

Case #2:Exposure of hospital staff and family• 23 family members including one who was

bitten• 32 of 79 health care workers (19 nurses, 4

physicians, 5 resp therapists, 2 XR techs, 2lab staff)

Human Rabies Cases, U.S.1980-2005

• 36/56 (64%) associated with insectivorousbat rabies virus variants

• Most do not have history of bat bite– Unreported minor bites– Hard to get history from rabies infected people– Unrecognized bites?– Teeth are small- no large wounds

Human rabies exposure/transmission

• Not all animal bites arerabies exposures.However all bites shouldbe evaluated … why?

• Transmission: infectious

saliva into skin or mucousmembrane.

Rabies is preventableEvaluation of animal bites

• Species?• Bite? Non-bite?• Place of exposure

– Foreign travel?– Other US, local

• How was the animalacting?

• Provoked/unprovoked?• Is animal available for

observation- (domesticanimal)or testing (wild)?

Post exposure prophylaxis

• Rabies is preventableif vaccine isadministered beforethe virus gets intonerve tissue.

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Unique rabies case, WI

• A 15 year old girl developed fatigue,tingling, numbness left hand; she becameunsteady and had double vision.

• Day 4: Worsening symptoms-hospitalization

• Day 6: history of unevaluated bat bite inchurch 4 weeks earlier

Recovery from rabies:

• Supportive care; infection control• Drug induced coma for 7 days, …

– Rise in neutralizing antibodies 1:32---1:2,048

• Day 33: Removed from ventilator• Day 36: Discharged to rehab unit• Slow recovery- learn to walk, speak, feed herself, …• Home ~ 3 months later.• She has neurological deficits

Potential Human Rabies Exposures

• International travelers can beexposed to canine rabies– Some areas are HIGH RISK.

• U.S.= National variability:- Some states report hundreds(NC=659; TX=913) of rabidanimals annually/ some report <10(WY, UT, OR, NV, LA, HI, ID)

Rabies Post-ExposureProphylaxis (PEP)

• Cleanse wound immediately.• When needed, administer PEP as soon after

exposure as possible.• Rabies immunoglobulin: one dose• 5 doses of rabies cell culture vaccine

Rabies Control and PreventionPublic Education

Animal Bites: Wash wounds and seekmedical consultation - especially thosefrom bats/wild animals and foreign dogs

Control rabies in pets:• Vaccinate pets• Keep pets away from wildlife (bats,

raccoons..)• Follow leash laws• Control strays

Wildlife:• Avoid contact with sick

and injured wild animals.• Don’t feed, handle or translocate

wildlife

Summary

• Rabies circulates in natural cycles in reservoir species ofwildlife, (U.S.= insectivorous bats, skunks, raccoons,foxes) and “spills over” into many other species.

• Reservoirs of rabies do not “carry” rabies- they becomeinfected and effectively transmit virus before they die.

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Summary• Rabies is a fatal disease- All animal bites

should be assessed carefully.

• Any potential human contact with a bat needstimely response.

• Be responsible about pets: vaccinate them.You don’t know when or where they’ll beexposed. (hiking, traveling, or even in thehouse!)

Summary

• Our understanding of the pathology andepidemiology of rabies is incomplete.

• Public health has a role in every aspect of thiscomplex zoonoses.

• Rabies is a model for zoonotic disease preventionand control.

• Movement of animals globally and nationallypresents constant risk.

http://www.cdc.gov/ncidod/dvrd/rabies/

Thanks