1. Rabies: To PEP, or not to PEP? That is the question.

2. Roadmap Epidemiology & pathobiology of rabies Pre-exposure series Exposure risk assessment Post-exposure prophylaxis Reporting Requirements Resources

3. EPIDEMIOLOGY

4. Rabies – The Disease Rabies has been around for centuries; described as early as 2300 B.C. Transmission is direct, primarily via inoculation by bite, with infectious virus present in saliva. The reservoir for rabies is the animal pool that circulates rabies virus (diverse species of mammals each with a specific strain). Rabies is >99% fatal once symptoms occur.

5. Still Considerable Concern About Rabies In… The U.S. CDC estimates that more than 1 million people per year worldwide require medical attention for animal bites (far fewer than occur) Over 7,000 cases of rabies in animals are reported to the CDC annually Although the number of post exposure treatments given in the United States each year is unknown, it is estimated to be about 40,000 And Montana ~1500 persons presented to ER due to bites or injuries received by animals On average 20 cases of rabies in animals are reported in Montana annually (>90% are bats, skunks) Number of post exposure treatments given in the Montana each year is newly reportable, and is estimated to be about >100 *Hospital discharge data is provided through the Montana Hospital Discharge Data System courtesy of the Montana Hospital Association. Data from 2010-2013. Codes 906, excluding arthropods.

6. Animal Rabies Distribution 2009-2014

7. PATHOBIOLOGY

8. Transmission/Pathogenesis Most commonly spread by bite contact between the rabid animal and the recipient Viral particles travel out from brain (centrifugal spread)  nerve cells  salivary glands  excretion = infectious Virus in salivary glands means end stage of the disease: death usually occurs within several days Incubation period: Usually 4 weeks; can range from 10 days to a year or more (??)

9. Neuronal retrograde viral transport is estimated at ~50 - 100 mm/day (Tsiang et al., 1991) US median incubation period is ~35 days 0 Scheme of Rabies Virus Pathogenesis

10. Signs and Symptoms Animals (domestic) Fearfulness Aggression Excessive drooling Difficulty swallowing Staggering Seizures Depression Self-mutilation Light sensitivity Animals (wildlife) Any of above Unusual behavior Nocturnal animal active during day Lose fear of humans Humans Early symptoms are non-specific Fever Headache General malaise Progresses to encephalitis or myelitis Autonomic instability Dysphagia Hydrophobia Paresis or paresthesia Progressive worsening neurologic signs Negative test for other etiologies of encephalitis

11. Rabies Human Deaths Annual human deaths worldwide are approximately 55,000; every 15 minutes a patient dies of rabies. 40-70% rabies victims are children under 15 years of age. Modern cell culture vaccines and animal control measures in developed countries have reduced the incidence of rabies deaths. In the United States, an average of 3 deaths per year since 1990. In Montana, 2 cases/deaths in 1996 & 97, both bat variants, no apparent “wounds”, one reported bat in house 30 days prior, other exposure unknown but had frequent animal contact as “trapper” CDC

12. PREVENTION & CONTROL

13. Humans Rabies Prevention: General Population Pre-exposure vaccination of domestic animals Avoid contact with wildlife reservoirs Prompt recognition and reporting of potential exposures to public health and medical community Public education Avoid animal bites Public policy Animal control

14. Pre-exposure Vaccination (Humans) Recommended for veterinarians, veterinary technicians, animal control officers, animal shelter workers, rabies lab personnel and persons working with wildlife Provides protection from unapparent exposures and when treatment is delayed Also recommended for persons spending 1 month or more in countries with endemic dog rabies and in which PEP would likely be significantly delayed to geographic distances/ lack of medical infrastructure

15. Pre-exposure Vaccination Protocol Three doses of vaccine administered on days 0, 7 and 21 or 28 Dosage: 1.0 ml administered IM in the upper deltoid Recommendations encourage titer checks for those at high and medium risks, 6 mos. and 2 years respectively, no titer check for lower risk workers with pre-exposure series. If absent, administer booster

16. CDC Recommended Pre-exposure Pre-exposure 3-dose series intramuscular or intradermal regimen day 0 7 21 or 28

17. Rabies is 100% Preventable Avoid animal bites Recognize signs of rabies in animals Vaccinate animals and humans Support appropriate testing Seek immediate wound care and treatment Role of medical professional Coordinate with local or state public health Encourage patients to seek treatment for even minor bites

18. EXPOSURE RISK ASSESSMENT

19. Prevention steps after an animal bite or other exposure: Wash the wound/site well with soap and water. Have the animal tested for rabies or observed. See a Doctor, even if the bite is very small. For non-bite consult with Doctor or contact public health. Assess need for tetanus booster. Contact, or ensure your provider contacts, your local health department for recommendations.

20. Administrative Rules of Montana – Department of Public Health Report “exposure to a human by a species susceptible to rabies infection” to local health department (37.114.203) Local health officer must investigate and inform individual whether or not treatment is recommended Must report treatment options to DPHHS Must also arrange for quarantine or testing of animal Additional requirements through Department of Livestock (ARM 32.3.1201 through 32.3.1207) describe management of animals and complement DPHHS rules.

21. Should Anti-Rabies Prophylaxis be Administered? CONSIDERATIONS: High or lower risk animal? Was there an exposure? Likelihood & timing for animal capture for confinement or testing. Epidemiology of rabies in your area.

22. Risk categories for animals in Montana HIGH RISK Bat Skunk Fox Cats -feral Groundhog LOW to NO RISK Squirrels, chipmunks Rats Mice, voles Indoor small caged pet rodents Lagomorphs Dogs Cats – vaccinated or not roaming Livestock – horses, cattle, pigs Other non-rodent wild animals species (opossum, bear, deer, coyote) MEDIUM RISK

23. Was There An Exposure? A bite (penetration of the skin by teeth) from a known or suspect rabid animal Scratches, abrasions, open wounds (bleeding within 24 hrs), or mucous membranes (eyes) contaminated with saliva or other potentially infectious material from a known or suspect rabid animal Other contact - such as petting an animal or contact with urine, feces or skunk spray - does NOT constitute an exposure Virus inactivated by Desiccation, Ultraviolet irradiation, Other environmental factors Does not persist in environment

24. Can The Biting Animal Be Confined & Observed? Healthy Healthy dogs, cats, ferrets may be confined and observed for 10 days after exposure Animal is monitored for signs of rabies, any illness must be evaluated by Vet which may lead to testing If healthy after observation period- animal was not capable of transmitting rabies at time of exposure Raccoons, skunks, fox, groundhogs and other wildlife cannot be observed- clinical signs of rabies in wild animals can not be interpreted reliably. Testing of the animal - or prophylaxis of bite victim - is always recommended after valid exposure unless a negative test is available Small rodent exposures- almost never require PEP

25. Considerations for Rabies PEP Medical urgency, not emergency Consult with LHJ Animal species and risk of infection Exposure evaluation Likelihood and timing for animal capture for confinement or testing Epidemiology of rabies in your area Requires advanced knowledge of rabies reservoirs International travel considerations

26. POST-EXPOSURE PROPHYLAXIS

27. Recommended Post Exposure Prophylaxis 1.Immediate flushing and washing of the wound with soap and water, or other detergent 2.Consult with public health 3.Passive immunization: Administration of Rabies immune globulin for contacts/exposures (HRIG) – immediate protection 4.Active immunization: Administration of tissue culture vaccine according to the CDC regimen – patient’s immune response

28. Rabies Postexposure (PEP) Two biologics are administered: 1.Human Rabies Immunoglobulin (HRIG) – confers immediate protection with antibodies vs. rabies 2.Rabies Vaccine - patient develops antibodies over a 2 to 4 week period

29. Where do you administer Immunoglobulin? A.Inject most of the IG around the wound and rest away from vaccine site B.Inject half around the wound, half on opposite side of body C.IG is not site specific D.In at least one arm and one leg ?

30. Where to administer Immunoglobulin? HRIG around or inside wound Remaining volume IM at site distant from vaccine 20 IU/kg body weight Never use same syringe as vaccine Do not administer more than necessary Do not administer after day 7 or dose 3 of vaccine HRIG around wound

31. Where to administer rabies vaccine? Deltoid only acceptable site for adults and older children Younger children anterolateral thigh okay Opposite of HRIG site Never at same site of HRIG Never in gluteal area deltoid anterolateral thigh gluteal

32. CDC Recommended PEP Schedule* Standard intramuscular regimen. One dose into deltoid on each of days: Rabies immunoglobulin day 0 3 7 14 No Rabies immunoglobulin needed day 0 3 Previously unvaccinated individuals Previously vaccinated individuals *reduced dose regimen recommended in 2010 Vaccine

33. What happens if you deviate from the schedule? Tom started undergoing PEP because he slept in a cabin with bats and the health department recommended pursuing PEP. He got his HRIG and 1 st dose of vaccine on day 0. After that initial visit, he spaced going back to the clinic on day 3 because he went on a camping trip with his friends over the weekend. The health department is trying to reach him, but it’s now day 5. What should they do? A.Restart series from beginning B.Continue with original dates of schedule C.Continue with same intervals between doses D.Any deviations from schedule are not too important, just as long as the shots are given around those days.

34. Deviations from the Schedule If deviation occurs, maintain original interval. Deviations of few days forgivable, longer needs assessment Example: If a patient misses the dose scheduled for day 7 and presents for vaccination on day 10, the day 7 dose should be administered that day and the schedule resumed, maintaining the same interval between doses. In this scenario, the remaining dose would be administered on days 17. When substantial deviations from the schedule occur, immune status should be assessed by per-forming serologic testing 7–14 days after administration of the final dose in the series.

35. Average Charges of PEP per person* MT claims >$100,000 annually paid $30,000/year *Data from Medicaid rabies 1/1/2010 to 2015 with a diagnosis code (071, 979.1, E949.1, V01.5, V04.5) or procedure code (90375, 90376, 90675, 90676, 90726, J2750) or ICD-9 surgical procedure code (09944) Amount charged for HRIG only Amount charged for rabies vaccine Amount charged for complete PEP $3,151 89% administered in hospital (  +$353 in ER visit fee) $485 (as high as $1,500 per dose) $5,146 (as high as $24,600)

36. Cost comparison 210lbs male150lbs female40lbs child20lbs monkey $1,800 $4,400 $3,400 HRIG + vaccine (x4) + wound cleaning + tetanus + admin = ??? HRIG + vaccine (x4) (wholesale only)

37. Where to order? 1.VaccineShoppe (www.vaccineshoppe.com)www.vaccineshoppe.com Sanofi Pasteur 2.Hospital pharmacy 3.Availability 4.Plan in place? 5.Standing order?

38. Uninsured and Underinsured Patient assistance programs that provide medications to uninsured or underinsured patients are available for rabies vaccine and Immune globulin. Sanofi Pasteur's Patient Assistance Program (providing Imogam ® Rabies-HT and Imovax ® Rabies as well as other vaccines) is now administered through the Franklin Group. (1-800-VACCINE) or (1-866-801-5655). Novartis' Patient Assistance Program for RabAvert ® is managed through RX for Hope (1-800-589-0837).

39. Key Rabies Information Resources Compendium of Animal Rabies Prevention and Control Human Rabies Prevention – U.S. Montana Code Annotated Administrative Rules of Montana Rabies Law Enforcement Guidelines Local public health practitioners Montana Department of Public Health and Human Services 24/7/365 public health consultation 406.444.0273 Montana Department of Livestock Animal rabies consultation 406.444.5214 http://dphhs.mt.gov/publichealth/cdepi/diseases/rabies.aspx

40. QUIZ

41. Rabies Question #1 A 53 y.o. immunocompromised man was bitten on the left thumb by a feral cat and now is in a local E.D. seeking the rabies PEP. The incident happened three days ago in Yellowstone County and the feral cat has not been located. It is unlikely that the biting cat will ever be found since there are many cats with the same coloration in the area. 1. Looking at the epi for rabies in that region what would your recommendation(s) be?

42. Rabies Answer #1 1. Lots of skunks in that area. Perfectly feasible for there to be a skunk/cat altercation and possible zoonotic transmission. Recommend PEP Assume no vaccine status of cat Cats can have rabies – symptomatic? Was the bite provoked? Cat can not be located. Can wait up to 10 days to locate Immunocompromised person…5 th dose.

43. Rabies Question #2 An Emergency Department physician contacts the On-Call epi about an incident involving a male camper whose foot was bitten by what he believes to have been a coyote while sleeping in his tent the night before. Several puncture wounds were noted on the camper’s right foot and the appropriate wound management administered. 1.What would the “appropriate wound management” include? 2.Would rabies PEP be recommended? Why? 3.If PEP is recommended, how should it be administered?

44. Rabies Answer #2 1.What would the “appropriate wound management” include? Standard care – clean and assess for a tetanus booster. 2.Would rabies PEP be recommended? Why? Can the patient be absolutely positive it was a coyote? (No) Does the patient remember the bite? (No) Can the coyote be located/tested? (No, but could wait up to 10 days to look for coyote if patient had a good description of the animal) Is there a history of rabid coyotes in the area? 3.If PEP is recommended, how should it be administered? Yes. (1) HRIG all around the bite site (dosage by body weight). Any remaining volume injected intramuscularly distant from vaccine site. Day 0 vaccine injected distant from HRIG. Day 3, 7, 14 at same location as HRIG.

45. Rabies Question #3 We have a female that will be traveling to the Amazon to work directly with bats in the very, very near future. She went through the rabies pre-exposure series in 2007. No serologic testing has been done since then. 1. What would you recommend be done to have her protected against rabies – if anything?

46. Rabies Answer #3 Patients who have previously received either pre or post- exposure rabies prophylaxis should receive only two rabies vaccine boosters following an exposure, given on days 0 and 3. Patients who have been previously vaccinated SHOULD NOT receive HRIG. Persons in risk group (laboratorians, researchers): rabies antibody every 2 years; if the titer low  single booster dose of vaccine. Testing or booster doses are not recommended for travelers. Rabies testing can takes at least 2 weeks depending on lab work load.

47. Please calculate volume of HRIG required for a 150lb female. 1.0.6 ml 2.3 ml 3.6 ml 4.9 ml 5.20 ml DOSE (ML): *20 (IU per kg) X weight (KG)/150 (IU per ml) 10lbs = 4.5 kg 2 ml vial = 300 IU 10 ml vial = 1500 IU

48. Questions?