# Presentation: 410885

## Human Rabies 

**Prevention and Control**

**Centers for Disease Control and Prevention**
**Rabies Section**
**Cathleen A. Hanlon, VMD, PHD**
**Veterinary Medical Officer**

## Slide 2

## 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.

## 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*.

## Cats....~275 - 300 cases/year

- Dogs.............~100 cases/year

## Slide 6

## Slide 7

## BackgroundRabies 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

**Notes:**
Rabies virus belongs to the family Rhabdoviridae, Rhabdo being taken from the Greek word for “rod” or “stick”.  This family has 2 genera, the Vesiculovirus genus and the genus Lyssavirus, for which rabies is the prototypic virus.  These are enveloped single-stranded, negative sense RNA viruses without a segmented genome, that cause a virtually (Wisconsin not with-standing) uniformly fatal encephalitis.

Historically, human cases in the US have most often been due to exposure via rabid dogs.  Like most developed countries, however, human cases are now more likely to be due to a wildlife exposure.  In the US, bats, raccoons and skunks are all reservoirs of rabies virus.  The US has ranged from 1-6 human cases/year over the past 13 years...all of which have been acquired from bats until 2003, when the first case of human rabies associated with the raccoon strain was found.  

## Rabies Pathogenesis

- Bite

- Incubation - non-infectious10 days – 6 months or possibly more

- Viral sheddingand illnesson the order of days

- Death

## Rabies Pathogenesis

- Brain infection – animal begins to act differently, including being driven to bite. Virus may be present in the saliva.

- Bite

- Incubation - non-infectious10 days – 6 months or possibly more

- Viral sheddingand illnesson the order of days

- Death

## 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).

## Animal Epizootiology 

- Animal Epizootiology

**   ****NC Skunk**

** ****TX Coyote**

**Raccoon**

**CA**
** ****Skunk**

** ****Arctic Fox**

**Red Fox**

**SC Skunk**

**NC SK**

**Rac**

**SC SK**

**G Fx**

**Fox**

**85%**

**80%**

**90%**

- Nucleotide Sequence Homology of Antigenic Variants (AV)

**TX Gray Fox**

**AZ  Gray Fox**

**CA SK**

## 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...

## Slide 14

## A-Z INDEX

**A-Z INDEX**

## Slide 16

## Professional resources

**Professional resources**

## Clinician information line877-554-4625

**Clinician information line****877-554-4625**

**1999 ACIP guidelines**

## 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

## Human rabies rule-out guidelines and forms

**Human rabies rule-out guidelines and forms**

## 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....

## Necessary conceptions.... Routes of exposure ...

- 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

## 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.

## 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

## 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

## 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.

## 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

## PEP – Previously immunized

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

## 16 day old infant

## 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

## Slide 31

## Bat-associated human rabies cases, 1980-2004 (n= 36)

- Bat-associated human rabies cases, 1980-2004 (n= 36)

**1980-89**

**1990-99**

**2000-04**

**Donor case**

**Notes:**
1980-89  Two cases
1990-99  20 cases
2000-04  14 cases, 10 naturally occurring

## Bats and the trivial bite story

**Eastern pipistrelle and Silver-haired bat**

- 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.

**Rabies-positive red bat (Lasuirus borealis)**

## Bat bite on finger

## 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 N=8
- Retrospective diagnoses
- CA, El Salvador immigrant, canine rabies virus variant
- FL, Haitian immigrant, canine rabies virus variant

**Notes:**
Last year was an unusual year in rabies.....

## 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: (517) 335-8120 
	RabAvert Intramuscular Purified chick embryo cell 
		Chiron Corporation vaccine (PCEC) Phone: CHIRON8 (800) 244-7668
Rabies immune globulin (RIG)
	 Imogam Rabies-HT 	Pasteur-Merieux Serum et Vaccins, Connaught Laboratories, Inc. 
 	BayRab 	Bayer Corporation Pharmaceutical Div. =======================================================

**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: (517) 335-8120
- 	RabAvert Intramuscular Purified chick embryo cell
- 		Chiron Corporation vaccine (PCEC) Phone: CHIRON8 (800) 244-7668
- Rabies immune globulin (RIG)
- 	 Imogam Rabies-HT 	Pasteur-Merieux Serum et Vaccins, Connaught Laboratories, Inc.
-  	BayRab 	Bayer Corporation Pharmaceutical Div. =======================================================

- Rabies Biologics

***Post-exposure prophylaxis (PEP) consists of  five doses of vaccine (days 0, 3, 7, 14, and 28) and one dose of RIG (day 0)***

## How did the donor become infected?

- Team visited the donor’s apartment complex
- Saw 2 bats (unable to identify species)
- Reports of bat problems from residents
- Physical evidence of past bat colonization
- Interviews with donor’s 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?

**Notes:**
The donor lived in a small town in Arkansas, close to the Texas border.  The investigative team arrived in Town A late in the evening and, after making contact with the state and local health department representatives, made a visit to the donor’s home...an apartment complex consisiting of several buildings, with approximately 8 apartment units per building.  While standing in front of the building where the donor’s unit had been, we witnessed 2 bats...one flying and one on the wall, under an eave of the roof... While we were there, other people, presumed residents, asked us if we were there because of the “bat problem”...further investigation revealed that the complex had had problems with bats over the past several years.  Additionally interviews with 2 of the donor’s friends revealed that the donor had mentioned an encounter with a bat...though the two friends differed in their recall of the timing.  It was not clear if this represented a single encounter with poor recollection of the time frame, or two different encounters...

## Donor Clinical Course

**Cc: “Fell out 3 times” per family & “Shallow breathing, wheezing”**
**Started to walk out and “pt dropped to his knees – eyes open”**
**H&P: “...is hyperventilating ...to the point that his fingers are spasming...”**
**“****He is very, very anxious.”**

- 24 Apr

**Party at local club**
**~100 persons**
**Sharing drinks & **
**Smoking materials**

- 27 Apr

- 28 Apr

**Nausea****Vomiting**

**0925: Hospital A ER**
**Cc: “can’t even swallow my spit”**
**“****Upon attempting to swallow, became nauseated and threw up levoquin”**
**DC Dx: Vomiting, Hypokalemia, UTI**
**       ****Tx:  Phenergan & Bactrim DS, bid**

**2213: Hospital B  (Admitted from ER)**
**Cc: Vomiting blood/Abd pain**
**H&P: “...agitated/confused/delerious...” in ER**
**           ****Intubated for airway protection**
**Labs: CPK elevated (3404)**
**    ****? Cocaine induced MI**
**Tox Screen: Positive for cannabinoids and cocaine**

- 03 May

- 29 Apr

**CT Head: Mild SAH**

- 01 May

**CT Head: Enlarged SAH**
**Tonsilar Herniation**

**Organs Harvested**

- 02 May

**Notes:**
This slide shows you the overall course of event for the donor...symptoms began on April 27th, and he initially presented on April 28th...

## 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...”

## Vital Signs

| Date | 4/28 | 4/29 | 4/30 | 5/1 | 5/2 | 5/3 |
| --- | --- | --- | --- | --- | --- | --- |
| Temp | 99.6 | 99.5 -101.8
 | 89.6 -106.5
 | 96.5 -101.1
 | 98.4 -100.6
 | 99.1-99.3
 |
| BP | 147/68 | 233/106 -
  67/34 | 174/103 -     61/35 | 258/28 – 66/30 | 178/126 -61/39 | 155/74 – 96/78 |
| HR | 66 | 118-194 | 112-176 | 102-136 | 114-124 | 114-120 |
| RR
On vent (AC) | 26 | 16 - 33 | 16-39 | 12-28 | 16-26 | 20 |

**Notes:**
This slide shows the donor’s autonomic instability...note wide fluctuations in temperature and blood pressure especially.  Though the patient’s heart rate also ranged somewhat, he was always tachycardic...

## Timeline of Events

**03 May**

**Donor ****Organs**
**Harvested**

**Kidney 1 Transplanted**

**Kidney 2 Transplanted**

**09 May**

**Liver Recipient**
**Discharged**

**Liver Recipient**
** ****Readmitted**
**Tremors, Lethargy **

**25 May**

**06 Jun**

**Liver Recipient**
** ****Dies **

**11 May**

**Kidney 1 Recipient**
**Discharged**

**Kidney 1 Recipient**
**Readmitted**
**Flank pain**

**29 May**

**Kidney 1 ****Recipient**
**Dies**

**08 Jun**

**Kidney 2 Recipient**
**Discharged**

**16 May**

**Kidney 2 Recipient**
**Readmitted:**
**Myoclonus, ****confusion**

**Kidney 2 ****Recipient**
**Dies**

**30 May**

**20 Jun**

**Timeline of Events**

**Second Liver Transplanted**

**05 May**

**10 Jun**

**Second ****Liver ****Recipient ****Dies**

## 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

**Notes:**
Laboratory confirmation can be made by a variety of techniques.  
Early diagnosis is preferable in order to minimize  rabies exposure to others.  Additionally, lack of a diagnosis of rabies cues the clinician to continue searching for a cause (hopefully, treatable) for the encephalitis.

## 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?

## 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?