1. RABIES Atilla Kiss M.D. Prepared by Kellie Zaylor D.O. January 4, 2006

2. Epidemiology In the Third World: An estimated 40- 70,000 people die from the disease each year In the Third World: An estimated 40- 70,000 people die from the disease each year Rare in U.S. Rare in U.S. –40 cases/year prior to vaccination of domestic animals that began in 1947 –3 cases/year now reported

3. Epidemiology World wide: Dogs most commonly infected and cause more transmission to humans World wide: Dogs most commonly infected and cause more transmission to humans Bats: An important source in North & South America and Mexico. Bats: An important source in North & South America and Mexico.

4. Epidemiology: United States In U.S.- >90% of rabies occurs in wild animals: Principal reservoirs are racoons, skunks, foxes and bats In U.S.- >90% of rabies occurs in wild animals: Principal reservoirs are racoons, skunks, foxes and bats

5. Rabies Carriers

6. Skunks & Racoons Eastern Seaboard: Rabies is endemic in racoons Eastern Seaboard: Rabies is endemic in racoons –Only one human case of rabies from a racoon variant has ever been documented (no history of exposure is known) North Central, South Central and California: Skunks are important carriers, each with its own regional viral strain North Central, South Central and California: Skunks are important carriers, each with its own regional viral strain

7. BATS Rabid bats account for 17% of all cases of rabies in U.S. animals Rabid bats account for 17% of all cases of rabies in U.S. animals Hawaii- is rabies-free. There are no rabid bats or rabid terrestrial animals. Hawaii- is rabies-free. There are no rabid bats or rabid terrestrial animals.

8. Human Cases Between 1990-2003: 39 cases diagnosed with 32 likely acquired in U.S. Between 1990-2003: 39 cases diagnosed with 32 likely acquired in U.S. –88% (28 cases) associated with bats –2 cases associated with the dog and coyote populations of Texas –1 with a racoon in VA. –1 with a mongoose in Puerto Rico

9. Human vs. Bat In most cases, history of bat contact was obtained after patient’s death. In most cases, history of bat contact was obtained after patient’s death. –In 3 cases: victim was aware of the bite, but didn’t seek rabies prophylaxis –In half of cases: victim had bat contact, but no bite history –No history of bat exposure for the remaining victims

10. Disease Principals Rabies is not a zoonosis: Animals that get infected will die. Rabies is not a zoonosis: Animals that get infected will die. –Death occurs within 3-9 days after they first begin secreting virus in their saliva. They can transmit the virus at this point. –Exceptions: Some animals can get sick before virus is found in saliva or may not become ill until several days after virus is secreted.

11. Disease Principals Bats can live 10 days after infection Bats can live 10 days after infection Has been suggested dogs can become asymptomatic carriers, but transmission from one has never been documented Has been suggested dogs can become asymptomatic carriers, but transmission from one has never been documented In U.S. all rabid dogs die within 8 days of becoming ill; median 3 days. In U.S. all rabid dogs die within 8 days of becoming ill; median 3 days.

12. Animal Behavior

13. Classic Picture of rabid, mangy dog foaming at the mouth…not often seen, signs frequently more subtle. Classic Picture of rabid, mangy dog foaming at the mouth…not often seen, signs frequently more subtle. Animals can display aggressive behavior, ataxia, irritability, anorexia, lethargy or excessive salivation. Animals can display aggressive behavior, ataxia, irritability, anorexia, lethargy or excessive salivation.

14. Animal Behavior Cats are more likely to be aggressive than dogs Cats are more likely to be aggressive than dogs Animals exhibit change in instinctive behavior: nocturnal animal walking around in daylight (i.e. raccoons) Animals exhibit change in instinctive behavior: nocturnal animal walking around in daylight (i.e. raccoons) Unprovoked bites Unprovoked bites

15. Transmission Almost all transmission is by bite Almost all transmission is by bite 50 times greater risk than a scratch 50 times greater risk than a scratch One human case may have been acquired in a laboratory (transmitted by aerosol) One human case may have been acquired in a laboratory (transmitted by aerosol)

16. Transmission In wild animals: Rabies can be transmitted transplacentally In wild animals: Rabies can be transmitted transplacentally Transplants in human- possible Transplants in human- possible Human-to-human: Never has been confirmed Human-to-human: Never has been confirmed Rabies virus never isolated from blood Rabies virus never isolated from blood

17. Virus lifestyle Virus replicated in muscle cells near site of bite for most of incubation time. Virus replicated in muscle cells near site of bite for most of incubation time. –Incubation time 30-90 days. Latency up to 7 years Then ascends along motor and sensory axons at rate of 12-100mm/day and has predilection for brainstem and medulla Then ascends along motor and sensory axons at rate of 12-100mm/day and has predilection for brainstem and medulla Enters salivary glands after replication in CNS. Enters salivary glands after replication in CNS.

18. Rabies virus Risk of developing rabies after a bite: 5- 80%. Risk of developing rabies after a bite: 5- 80%. –Depends upon….  Severity of exposure  Location of the bite  The biting animal  **Bites on head and neck have shorter incubation time (as short as 15 days) because of rich peripheral nerve supply

19. Clinical Features Prodrome: HA, fever, rhinorrhea, sore throat, myalgias, GI upset. *Back pain and muscle spasms. Prodrome: HA, fever, rhinorrhea, sore throat, myalgias, GI upset. *Back pain and muscle spasms. Agitation and anxiety may result in diagnosis of psychosis or intoxication Agitation and anxiety may result in diagnosis of psychosis or intoxication Paresthesias, pain or severe itching at site may be the first neurological symptom. Paresthesias, pain or severe itching at site may be the first neurological symptom.

20. Clinical Features Over several days symptoms progress Over several days symptoms progress Rabies takes two forms: Rabies takes two forms: “Furious”/Encephalitic form: agitation, hydrophobia, extreme irritability, hyperexcitability periods fluctuate with lucidity. “Furious”/Encephalitic form: agitation, hydrophobia, extreme irritability, hyperexcitability periods fluctuate with lucidity.  Vitals abnormal: tachycardia, tachypnea, fever

21. Encephalitic Form Hydrophobia: Patient can’t swallow because violent jerky contraction of diaphragm and accessory muscles of inspiration when pt attempts to swallow liquids Hydrophobia: Patient can’t swallow because violent jerky contraction of diaphragm and accessory muscles of inspiration when pt attempts to swallow liquids - Patients will be terrified during this reaction and may even experience this at the sight of water or if water touches their face.

22. Encephalitic Form Aerophobia: an extreme fear of air in motion can be elicited from some patients. This can also cause violent muscle spasms in the neck and pharynx. Aerophobia: an extreme fear of air in motion can be elicited from some patients. This can also cause violent muscle spasms in the neck and pharynx. Hallucinations, seizures, ataxia, focal weakness and arrhythmias can occur. Hallucinations, seizures, ataxia, focal weakness and arrhythmias can occur.

23. Paralytic Rabies Other form is “dumb” or paralytic rabies. Similar to Guillain-Barre. Other form is “dumb” or paralytic rabies. Similar to Guillain-Barre. –Prominent limb weakness. Consciousness initially spared Two forms can overlap or progress from one to the other Two forms can overlap or progress from one to the other Coma after one week of neuro symptoms with death a few days after. Coma after one week of neuro symptoms with death a few days after.

24. Management Once symptoms occur: fatal in 3-10 days Once symptoms occur: fatal in 3-10 days ICU support: can prolong 4 months. ICU support: can prolong 4 months. Six patients have survived clinical rabies: 5 had pre or postexposure prophylaxis before onset of symptoms Six patients have survived clinical rabies: 5 had pre or postexposure prophylaxis before onset of symptoms

25. Clinical Case In Wisconsin 2004: 15 year old girl bitten on left index finger by a bat after picking it up off a floor and releasing it outside of her church. In Wisconsin 2004: 15 year old girl bitten on left index finger by a bat after picking it up off a floor and releasing it outside of her church. Pt cleaned wound with hydrogen peroxide but did not seek help because the belief that sick/rabid bats could not fly. Pt cleaned wound with hydrogen peroxide but did not seek help because the belief that sick/rabid bats could not fly.

26. Clinical Case 1 month after bite, c/o fatigue, parasthesias in left hand. Two days later: unsteady, diploplia, nausea/vomiting. 1 month after bite, c/o fatigue, parasthesias in left hand. Two days later: unsteady, diploplia, nausea/vomiting. Referred to neuro from pediatrician: MRI/MRA normal and sent home. Referred to neuro from pediatrician: MRI/MRA normal and sent home.

27. Clinical Case Fourth day of illness: symptoms cont’d. Admitted for LP and supportive care. Fourth day of illness: symptoms cont’d. Admitted for LP and supportive care. –CSF: wbc 23 cells –93% lymphocytes –RBC 3 cells –Protein 50 mg/dL –Glucose 58 mg/dL

28. Clinical Case Over next 36 hours: slurred speech, nystagmus, tremors in left arm, lethargy, temp of 102. Over next 36 hours: slurred speech, nystagmus, tremors in left arm, lethargy, temp of 102. Sixth day: bat-bite history reported and rabies considered in differential and transferred to tertiary care center. Sixth day: bat-bite history reported and rabies considered in differential and transferred to tertiary care center. Upon arrival: Temp 100.9, impaired muscle coordination, difficulty speaking, double vision, muscle twitching, tremors, obtunded. Upon arrival: Temp 100.9, impaired muscle coordination, difficulty speaking, double vision, muscle twitching, tremors, obtunded.

29. Clinical Case Blood, CSF, nuchal skin samples, saliva submitted to CDC. Blood, CSF, nuchal skin samples, saliva submitted to CDC. Pt developed hypersalivation and was intubated. Pt developed hypersalivation and was intubated. Rabies-virus specific antibodies were detected in serum and CSF. No evidence found in nuchal skin biopsies and saliva. Rabies-virus specific antibodies were detected in serum and CSF. No evidence found in nuchal skin biopsies and saliva.

30. Clinical Case Management: drug-induced coma and ventilator support for 7 days Management: drug-induced coma and ventilator support for 7 days IV ribavirin IV ribavirin CSF antirabies IgG: from 1:32 to 1:2,048 CSF antirabies IgG: from 1:32 to 1:2,048 Meds tapered, on 33 rd day of illness, extubated, 3 days later transferred to rehab. Meds tapered, on 33 rd day of illness, extubated, 3 days later transferred to rehab. Unable to speak, could walk with assistance and feed herself. Unable to speak, could walk with assistance and feed herself. Prognosis for her full recovery is unknown. Prognosis for her full recovery is unknown.

31. Management No effective treatment exists. No effective treatment exists. Postexposure Prophylaxis/PEP: 3 steps Postexposure Prophylaxis/PEP: 3 steps –1. Wound care: immediate thorough washing with soap and water and a virucidal agent such as povidine-iodine or 1-2% benzalkonium chloride.  Shown to be protective if performed within 3 hours of exposure  If puncture, swab deeply in wound and around edges

32. PEP 2. Passive Immunization: Human rabies immunoglobulin (HRIG) 20 IU/kg ASAP, but not longer than 7 days after vaccine given. Infiltrate entire dose around wound, any remaining IG inject IM at a site distant from the vaccine. 2. Passive Immunization: Human rabies immunoglobulin (HRIG) 20 IU/kg ASAP, but not longer than 7 days after vaccine given. Infiltrate entire dose around wound, any remaining IG inject IM at a site distant from the vaccine. 3. Human diploid cell vaccine (HDCV): 1 ml (deltoid) on days 0,3,7,14,28. 3. Human diploid cell vaccine (HDCV): 1 ml (deltoid) on days 0,3,7,14,28.

33. PEP Vaccine: do not give in gluteal. If injected into fat, no antibodies formed. Vaccine: do not give in gluteal. If injected into fat, no antibodies formed. HRIG and HDCV: give in different anatomical sites and never in the same syringe. HRIG and HDCV: give in different anatomical sites and never in the same syringe.

34. PEP Local Reactions: itching, erythema, pain, swelling Local Reactions: itching, erythema, pain, swelling Systemic: HA, myalgia, nausea. Systemic: HA, myalgia, nausea. Anaphylaxis:.1% of cases Anaphylaxis:.1% of cases Guillain-Barre: 3 cases Guillain-Barre: 3 cases Angiodema: 6% of pts who receive boosters. Angiodema: 6% of pts who receive boosters. Can give PEP during pregnancy Can give PEP during pregnancy

35. Who should get PEP? Type of exposure Type of exposure Location of incident (head/neck) Location of incident (head/neck) Species of biting animal (common carrier of rabies?) Species of biting animal (common carrier of rabies?)

36. WHAT IS A SIGNIFICANT EXPOSURE?

37. Significant Exposure

39. Bites are significant Bites are significant Nonbite exposures that involve contamination of either mucous membrane or open wound (bled within 24 hours) with saliva Nonbite exposures that involve contamination of either mucous membrane or open wound (bled within 24 hours) with saliva Not significant: petting a rabid animal, contact with its blood, urine, feces. Not significant: petting a rabid animal, contact with its blood, urine, feces. –Skunk spray –Dry virus: NOT INFECTIOUS

40. Animals in captivity Wild animals that are caught should by euthanized immediately and head sent under refrigeration to an appropriate lab for testing. Wild animals that are caught should by euthanized immediately and head sent under refrigeration to an appropriate lab for testing. Domestic animals that are apparently healthy should be observed for 10 days. If animal doesn’t become ill, victim does not require treatment. Domestic animals that are apparently healthy should be observed for 10 days. If animal doesn’t become ill, victim does not require treatment. –If animal gets sick, euthanize and test immediately.

41. References Chapter 129: Rabies. Rosen’s Emergency Medicine Chapter 129: Rabies. Rosen’s Emergency Medicine CDC : http://www.cdc.gov/ncidod/dvrd/rabies CDC : http://www.cdc.gov/ncidod/dvrd/rabieshttp://www.cdc.gov/ncidod/dvrd/rabies http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm5350a1.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm5350a1.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm5350a1.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/ mm5350a1.htm WHO: WHO: http://www.who.int/mediacentre/factsheet/fs099/ en http://www.who.int/mediacentre/factsheet/fs099/ en