Human Rabies

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Human Rabies Prevention and Control
Centers for Disease Control and Prevention Rabies
Section Cathleen A. Hanlon, VMD, PHD Veterinary
Medical Officer
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Common misconceptions. Dogs and rabies

• Worldwide dogs are the most important and
  common source of human exposure.
• Dog rabies remains uncontrolled in many parts of
  Africa and Asia.
• This is no longer true in the USA and many other
  parts of the world where vaccination of dogs and
  control of strays has eliminated the canine
  rabies virus variant.

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Common misconceptions. Dogs bites and urgent
human prophylaxis

• In the USA, when a dog, cat or ferret has bitten
  or otherwise potentially exposed someone and is
  available for observation or euthanasia and
  testing, the need for human rabies post-exposure
  prophylaxis should be based on the outcome of the
  10-day observation period or the laboratory
  result.

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What is the most common rabid domestic
animal.and less likely to be vaccinated or
confined?
Cats.275 - 300 cases/year Dogs.100
cases/year
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BackgroundRabies Virus

• Single-stranded RNA virus
• Non-segmented genome
• Prototype virus for genus Lyssavirus
• Neurotropic, causes fatal encephalitis
• Historically, dogs were the most common source
• Currently, most cases occur in wildlife species
• 2003 first report of human case due to raccoon
  variant
• Most common sources of human rabies cases in the
  US
• bat rabies virus variants

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Rabies Pathogenesis
Viral sheddingand illnesson the order of days
Bite
Incubation - non-infectious10 days 6 months or
possibly more
Death
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Rabies Pathogenesis
Brain infection animal begins to act
differently, including being driven to bite.
Virus may be present in the saliva.
Viral sheddingand illnesson the order of days
Bite
Incubation - non-infectious10 days 6 months or
possibly more
Death
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Common misconceptions. Rabies is rabies is
rabies

• There are many different rabies viruses.
• These are termed rabies virus variants or strains
  of rabies.
• They can be differentiated by monoclonal antibody
  reaction patterns (antigenic differences) and by
  differences in genetic sequences.
• Rabies virus variants are usually maintained in a
  single host reservoir species, although they may
  be transmitted to any susceptible mammal (i.e.,
  spillover).

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Animal Epizootiology
Fox
G Fx
Arctic Fox
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NC Skunk
NC SK
Red Fox
CA Skunk
80
CA SK
Raccoon
Rac
85
AZ Gray Fox
TX Gray Fox
SC Skunk
SC SK
TX Coyote
Nucleotide Sequence Homology of Antigenic
Variants (AV)
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Rabies Virus Variants in the USA

• A number of rabies virus variants are associated
  with an array of various species of insectivorous
  bats (between 15 and 30)
• Raccoon rabies virus variant
• Northcentral USA skunk rabies virus variant
• Southcentral USA skunk rabies virus variant
• CA skunk rabies virus variant
• Gray Fox rabies virus variant two different
  foci - AZ and TX
• Occasional incursions of dog/coyote rabies virus
  variant from Mexico into TX
• Arctic fox rabies
• Mongoose rabies in Puerto Rico

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A-Z INDEX
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Professional resources
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Clinician information line877-554-4625
1999 ACIP guidelines
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Primary Reference Documents

• ACIP Guidelines
• Human Rabies Prevention United States, 1999,
• Recommendations of the Advisory Committee on
  Immunization Practices
• Rabies Compendium
• Compendium of Animal Rabies Prevention
• and Control, 2004

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Human rabies rule-out guidelines and forms
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Common questions

• Human post-exposure prophylaxis
• Is the patient potentially exposed?
• Correct administration
• Infiltration of HRIG at the site
• Vaccine schedule (days 0, 3, 7, 14, 28)
• Whether or not to wait for the 10 day observation
  of dogs, cats and ferrets or the outcome of lab
  testing of these and other species.

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Necessary conceptions. Routes of exposure

• Bite is the most natural and successful way to
  transmit rabies.
• Exposing fresh, open bleeding wounds to live
  virus (i.e., fresh saliva or tissue)
• Oral exposure (consuming large amounts of live
  virus) may result in rabies but the risk is
  orders of magnitude lower.
• Inhalation of droplets or an aerosol
• Ocular not documented except with corneal
  transplant

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What is an exposure to rabies

• Rabies is transmitted only when the virus is
  introduced into bite wounds or open cuts in skin
  or onto mucous membranes.
• Bite - Any penetration of the skin by teeth
  constitutes a bite exposure.
• All bites, regardless of location or the minor
  nature of injury (such a those from bats),
  represent a potential risk of rabies
  transmission.
• Nonbite exposures from terrestrial animals rarely
  cause rabies.
• large amounts of aerosolized rabies virus (2 lab
  cases, 2 cases in a cave setting)
• surgical recipients of corneas (and organs)
  transplanted from infected donors
• The contamination of open wounds, abrasions,
  mucous membranes, or theoretically, scratches,
  with saliva or other potentially infectious
  material (such as neural tissue) from a rabid
  animal also constitutes a nonbite exposure.
• Other contact by itself, such as petting a rabid
  animal and contact with blood, urine, or feces
  (e.g., guano) of a rabid animal, does not
  constitute an exposure and is not an indication
  for prophylaxis. Because the rabies virus is
  inactivated by desiccation and ultraviolet
  irradiation, in general, if the material
  containing the virus is dry, the virus can be
  considered noninfectious.

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Post-exposure Prophylaxis (PEP)

• A medical urgency (but not an emergency)
• Local and state public health professionals are
  experienced in local epizootiology
• Complex decision
• Animal species
• Type of exposure
• Bite versus nonbite
• Availability of animal for rabies testing or
  observation

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Considering the need for PEP

• Dogs, cats, ferrets
• - if available, observe for signs of rabies for
  10 days
• - if remains healthy, cannot have transmitted
  rabies
• - PEP needed if animal tests positive, or not
  available for observation
• Wild carnivores (skunks, raccoons, fox), bats
• - high risk, test animal or PEP needed
• Livestock, small rodents, rabbits
• - low risk, treat on a case-by-case basis,
  consult with local and state health officials

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Common misconceptions. Rodents and rabies

• Rodents have never been a reservoir for rabies.
  Naturally infected cases are rare.
• Scenarios leading to infection of ..
• .domestic rodents are rabbits housed in outdoor
  hutches, often with a history of a wound.
• .large bodied, wild rodents (beavers and
  groundhogs (woodchucks)) in areas with raccoon
  rabies virus variant.

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Human PEP

• Local wound care wash immediately with soap and
  water
• HRIG dose according to body weight
• Infiltrate as much as possible at the site of the
  exposure remaining volume intramuscularly
• Five doses of vaccine IM deltoid
• Do not mix with HRIG or administer near HRIG site
• Days 0, 3, 7, 14, and 28

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PEP Previously immunized

• Two booster doses of vaccine
• IM deltoid
• Days 0 and 3
• HRIG is contraindicated

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16 day old infant
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Fundamentals

• Rabies is invariably lethal.
• There are a few survivors but extremely rare.
• Trends in the USA most human cases occurring
  due to lack of prophylaxis
• Exposure abroad, usually in country of origin
• Exposure to a bat and unaware or dismissive of
  the risk of rabies

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Bat-associated human rabies cases, 1980-2004 (n
36)
1980-89
1990-99
2000-04
Donor case
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Bats and the trivial bite story
Most human rabies cases acquired in the USA are
due to rabies virus variants associated with
insectivorous bats and, in particular, a specific
variant associated with Eastern pipistrelle and
Silver-haired bats. Insectivorous bats are small
less than 20 grams with tiny needle-like
teeth. Trauma alone, from a bat bite, is unlikely
to send anyone to an emergency room. For example,
an adult male dismissed a bite from a bat and
decided that the risk of rabies in bats was small
enough to not seek post-exposure prophylaxis. He
died of rabies several weeks later.
Eastern pipistrelle and Silver-haired bat
Rabies-positive red bat (Lasuirus borealis)
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Bat bite on finger
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2004 An unusual year in rabies

• Human rabies vaccine recall
• leaving only one on the market
• Organ transplant cases
• Donor and 4 recipients
• Rabies suspect sheep at a petting zoo
• Over 750 persons with one available vaccine
• Wisconsin human rabies case
• 15-year-old survivor with a history of a bat bite
• 2004 Total human rabies cases N8
• Retrospective diagnoses
• CA, El Salvador immigrant, canine rabies virus
  variant
• FL, Haitian immigrant, canine rabies virus variant

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Rabies Biologics

• TABLE 1. Rabies biologics -- United States, 1999
• Human rabies vaccine
• Imovax Rabies Intramuscular Human diploid cell
  vaccine
• Pasteur-Meriux Serum et Vaccins, (HFCV)
  Connaught Laboratories, Inc.
• Imovax Rabies I.D. Intradermal
• Rabies vaccine adsorbed (RVA) Intramuscular
• BioPort Corporation Phone [phone]
• RabAvert Intramuscular Purified chick embryo
  cell
• Chiron Corporation vaccine (PCEC) Phone
  CHIRON8 [phone]
• Rabies immune globulin (RIG)
• Imogam Rabies-HT Pasteur-Merieux Serum et
  Vaccins, Connaught Laboratories, Inc.
• BayRab Bayer Corporation Pharmaceutical Div.
  
  

Post-exposure prophylaxis (PEP) consists of five
doses of vaccine (days 0, 3, 7, 14, and 28) and
one dose of RIG (day 0)
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How did the donor become infected?

• Team visited the donors apartment complex
• Saw 2 bats (unable to identify species)
• Reports of bat problems from residents
• Physical evidence of past bat colonization
• Interviews with donors contacts
• Friend A
• Donor said bat had swooped down at him
• ? Occurred 1 month prior to death?
• Friend B
• Donor had said something about a bat
• Wanted to show site on clavicle where bat bit
  him
• ? Occurred 6 months prior to death?

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Donor Clinical Course
24 Apr
27 Apr
28 Apr
03 May
29 Apr
01 May
02 May
CT Head Enlarged SAH Tonsilar Herniation
Organs Harvested
Party at local club 100 persons Sharing drinks
Smoking materials
CT Head Mild SAH
0925 Hospital A ER Cc cant even swallow my
spit Upon attempting to swallow, became
nauseated and threw up levoquin DC Dx Vomiting,
Hypokalemia, UTI Tx Phenergan Bactrim
DS, bid
NauseaVomiting
1809 Hospital A ER Cc Fell out 3 times per
family Shallow breathing, wheezing Started to
walk out and pt dropped to his knees eyes
open HP is hyperventilating to the point
that his fingers are spasming He is very, very
anxious.
2213 Hospital B (Admitted from ER) Cc Vomiting
blood/Abd pain HP agitated/confused/delerious
in ER Intubated for airway
protection Labs CPK elevated (3404) ?
Cocaine induced MI Tox Screen Positive for
cannabinoids and cocaine
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Clinical Descriptions

• 4/29 "Hypertensive crisis/Seizure.pinpoint
  pupils
• 4/30 Patient thrashing Patient biting ETT
• 5/1 Ongoing seizures despite dilantin, benzos,
  phenobarb"
• "Pupils 8 mm...nonreactive..
• "Despite being loaded with 1gm Dilantin/ 1 gram
  phenobarb, Ativan Valium, pt has continued to
  have obvious motor activity even on Diprivan

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Vital Signs
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Timeline of Events
Liver Recipient Readmitted Tremors, Lethargy
Liver Recipient Dies
Kidney 1 Recipient Readmitted Flank pain
Kidney 1 Recipient Dies
Kidney 1 Transplanted
Donor Organs Harvested
Kidney 2 Transplanted
Kidney 2 Recipient Dies
Kidney 2 Recipient Readmitted Myoclonus,
confusion
Second Liver Transplanted
Liver Recipient Discharged
Second Liver Recipient Dies
Kidney 1 Recipient Discharged
Kidney 2 Recipient Discharged
09 May
25 May
11 May
16 May
30 May
06 Jun
05 May
20 Jun
29 May
08 Jun
03 May
10 Jun
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Laboratory Diagnosis

• Antemortem testing recommended
• To obtain a definitive diagnosis
• Minimize rabies exposure to others
• Testing methods
• Direct Fluorescent Antibody fresh skin or brain
• Modified for formalin-fixed tissue
• Anti-rabies antibodies - sera and CSF
• Reverse Transcriptase Polymerase Chain
  Reactiongenetic sequencing of products
• Immunohistochemistry
• Viral Isolation mouse inoculation or cell
  culture

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Unresolved issues

• Unrecognized infection promote awareness
• Screening prior to organ donation
• Diagnostic tests are available
• Retrospective diagnosis on cases of encephalitis
• Diagnostic tests exist capacity is possible
• Altered pathogenesis novel exposure sources
• Immunosuppression
• Surgical implantation and drainage sites
• Vaccine and RIG supplies
• Critical need
• Comprehensive oversight of transplant outcomes?
• Would these cases had been diagnosed if they had
  not occurred at the same facility?

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The Future

• Continued epizootic among raccoons
• Effect of oral vaccination for control of
  wildlife rabies?
• Increase in human rabies due to bat variants
• Unique viral characteristics of the most common
  variant acquired by humans
• Descriptive epidemiologic studies of PEP trends?
• Questions about availability of human rabies
  biologics
• Novel alternatives to HRIG?
• Imported animal rabies and potential for new
  epizootics
• Newly-identified Lyssavirus in Australia and Asia
• Heightened surveillance for newly emergent
  variants?
• Development of therapeutics?