1. Rhabdoviruses HUMAN RABIES
Professor Sudheer Kher

2. DEFINITION Rabies is an acute, progressive encephalomyelitis
The case to fatality rate is the highest of any infectious disease
One of the oldest described diseases
The leading viral zoonosis as regards global public health significance

3. Etiology - RABIES VIRUS
Rhabdoviridae family
Lyssavirus genus
helical, enveloped
ss RNA, -VE sense
Bullet shaped

4. BURDEN More than ~55,000 human rabies deaths per year
Most occur in developing countries
Millions of human exposures per year
The domestic dog is the single most important animal reservoir
Wildlife important, especially in developed countries

5. SC DHEC: FOR IMMEDIATE RELEASE Aug. 8, 2005
Upstate residents warned of potential for rabies in bats
COLUMBIA – Two men and a woman are being treated to prevent rabies as a precautionary measure after finding a rabid bat in a home near Greenwood, the S.C. Department of Health and Environmental Control said today. Although there was no known direct exposure, the bat could have been in the home long enough to bite the residents in their Greenwood County home near the McCormick County border. They are under the care of a physician.
“People usually know when they have been bitten by a bat,” said Sue Ferguson of DHEC’s Bureau of Environmental Health. “However, bats have small teeth, which may leave marks not easily seen and some situations require that you seek medical advice even in the absence of an obvious bite wound.
For example, if you awaken and find a bat in your room, or if you see a bat in the room of an unattended child, or near a mentally impaired or intoxicated person, we recommend that you seek medical advice and have the bat tested for rabies.
According to Ferguson, domestic animals also are at risk of rabies if they come in contact with infected wild animals, including bats.
“If you think your pet or domestic animal might have been bitten by a bat, contact a veterinarian or the Environmental Health Office at the DHEC Public Health Department in your county for assistance immediately and have the bat tested for rabies,” Ferguson advised. “State law requires that all pets be vaccinated against rabies, so remember to keep vaccinations current for cats, dogs, and other animals to protect both your family and your pets.”
FOR IMMEDIATE RELEASE Aug. 4, 2005
Five being treated after pet confirmed rabid
COLUMBIA – Three family members and two other adults in Dorchester County are being treated to prevent rabies after a pet kitten was confirmed to have rabies, the S.C. Department of Health and Environmental Control said today.
The kitten was given to a family that lives near Summerville about three weeks ago and was taken to a vet when it began acting ill. The DHEC lab on Wednesday confirmed it had rabies.
FOR IMMEDIATE RELEASE July 29, 2005 Beaufort County resident exposed to rabid raccoon COLUMBIA – Beaufort County residents are being urged to be aware of the potential for rabies in animals as a result of a Hilton Head woman who was exposed to a rabid raccoon July 26, the S.C. Department of Health and Environmental Control reported today.
The woman was bitten while attempting to rescue the raccoon that had been struck by a car on Beach City Road in Hilton Head. The woman is undergoing treatment by a physician.
Laboratory tests conducted by DHEC confirmed the raccoon was rabid.

6. RABIES HOSTS
All warm-blooded vertebrates are susceptible to experimental infection
Mammals are the natural hosts of rabies
Reservoirs consist of the Carnivora (canids, skunks, raccoons, mongoose, etc.) and Chiroptera (bats)

7. ANIMAL RESERVOIRs DOGS MONGOOSE (main reservoir in RSA in the wild)
SURICATE
JACKAL
BAT (some evidence to suggest carrier status and droplet infection)
FOX (in Europe)
SKUNKS, RACCOONS (in USA)
SEMI-WILD DOGS (in Natal)

8. TRANSMISSION BITE - USUAL ROUTE CORNEAL AND OTHER TRANSPLANTS
MUCOSAL MEMBRANES, WOUND
AEROSOL (RARE)

9. HUMAN RABIES HUMAN-TO-HUMAN surgically - via transplants
no direct human-to-human ever documented

10. RABIES PATHOGENESIS Virus is transmitted via bite
Agents are highly neurotropic
Enter peripheral nerves
Centripetal travel by retrograde flow in axoplasm of nerves to CNS
Replicate in brain
Centrifugal flow to innervated organs, including the portal of exit, the salivary glands
Viral excretion in saliva

11. Note: No viremia
Murray et al., Medical Microbiology

12. CLINICAL STAGES
Incubation Period (range = ~<7 days to >6 years; average is ~4-6 weeks)
Prodromal Phase (Non-specific signs)
Acute Neurological Phase
Coma
Death (recovery from rabies?)

13. SYMPTOMS Variable, often misdiagnosed
Tingling, paresthesia at bite site
Fever, headache, malaise, anorexia
Nausea, vomiting, myalgia, hydrophobia
Confusion, hallucinations, seizures, paralysis
Coma, respiratory failure, death

14. Clinical Presentation
Furious Rabies
Headache, fever, irritability, restlessness and anxiety. muscle pains, salivation and vomiting.
After a few days to a week the patient may experience a stage of excitement and be wracked with painful muscle spasms, triggered sometimes by swallowing of saliva or water. Hence they drool and learn to fear water (* Hydrophobia).
The patients are also excessively sensitive to air blown on the face. The stage of excitement lasts only a few days before the patient lapses into coma and death.
Once clinical disease manifests, there is a rapid, relentless progression to invariable death, despite all treatment.

15. Clinical Presentation
Dumb Rabies
Starts in the same way, but instead of progressing into excitement, the subject retreats steadily and quietly downhill, with some paralysis, to death. Rabies diagnosis may easily be missed.

16. Dumb rabies
Seen in occasionally in animals like dogs. The animal is paralysed, not aggressive. Saliva is infective.
Carrier state in animals – Not common but has been reported.
Implication – Vaccination essential even after exposure to non-rabid dogs/animals.

17. RABIES RECOVERY?
Five historical human case recoveries, after vaccination, but before illness onset
Only one documented unvaccinated human survivor after clinical presentation

18. Fixed Vs Street Virus
Freshly isolated virus from human/animals is called Street virus. Highly virulent.
Virus after serial passages in rabbit brain / tissue cultures is called as Fixed virus. Less virulence and hence used for vaccine production.

19. RABIES DIAGNOSIS
Based upon history of animal exposure and typical neurological clinical signs
Postmortem demonstration of viral antigen in CNS is gold standard
In humans, antemortem detection of virus or viral amplicons, antibodies, or antigens (sera, csf, saliva, nuchal biopsy)

20. DIAGNOSIS
By assessment of:
1.Bite - Geographical area, type of animal, severity and site of bite.
2. Animal
Live - observe in cage:
If survives > 8 days, then NOT rabies.
Dead - brain sent to Ref Virology Lab
- Negri bodies
- IFA
virus isolation
Man
Live - difficult diagnosis
- clinical picture, skin biopsy, corneal impression (antibodies only appear very late)
Dead - brain sent to Virology Lab
"Negri bodies" in cytoplasm of brain cells;
immunofluorescence virus isolation

21. DIAGNOSIS neutralizing antibodies in serum or CSF
direct fluorescence antibody
nuchal biopsy (nape of neck), brain biopsy
RT-PCR saliva
post-mortem staining of brain slice
Negri bodies (not always seen)

22. The Negri body Inclusion body
Stain used Seller’s stain – Basic fuchsin + Methylene blue in methanol.
3-27 µ, intracytoplasmic, round or oval, purplish pink structures with inner basophilic granules.

23. FLUORESCENT ANTI-RABIES NUCLEOPROTEIN ANTIBODY
Rabies virus infected
Uninfected
CDC

24. Rabies virus infected
Uninfected
CDC

25. Rabies virus infected - Negri body - note dark blue basophilic granules (Seller’s stain)
CDC

26. RABIES EXPOSURE Bite (common cause) Non-bite (rarely causes rabies)
Contacts with blood, urine, feces, etc. are not considered exposure
Many scenarios, such as merely seeing a rabid animal, being in the same room, petting, etc., are not considered grounds for prophylaxis
A small bat bite on a finger

27. PROPHYLAXIS
Pre-exposure Vaccination
Postexposure Prophylaxis (PEP)

28. RABIES BIOLOGICALS Rabies Vaccines (for pre- and PEP)
Rabies immune globulin (only in PEP)

29. Available vaccines Neural Vaccines – 5% Sheep brain suspension
Semple – Inactivated by phenol
BPL – Inactivated β propiolactone
Mouse Infant brain
Non-neural –
Egg vaccine Duck / Chick Embryo
Cell culture
Human diploid cell vaccine (HDCV) _ Commonly used.
Purified Vero cell culture vaccine (PVCV)
Purified chick embryo cell vaccine (PCECV)

30. PRE-EXPOSURE VACCINATION
Provided to subjects at risk before occupational or vocational exposure to rabies
VETERINARIANS AND STAFF
WILDLIFE OFFICERS ETC LIKELY TO CONTACT RABID ANIMALS
TRAVELERS LIKELY TO BE AT RISK
RABIES RESEARCH WORKERS
Simplifies postexposure management

31. PRE-EXPOSURE VACCINATION
Vaccine given on days 0, 7, and 21 or 28
Serology occurs every 6 months to 2 years (if remaining at risk)
If antibody titer not adequate, administer a single booster dose
If ever exposed, give a vaccine dose on days 0 and 3, regardless of titer

32. POSTEXPOSURE PROPHYLAXIS
Provided to subjects after rabies exposure
Consists of wound care, rabies immune globulin, and vaccine
If prompt and proper, survival virtually assured

33. POSTEXPOSURE PROPHYLAXIS
Wash lesions well with soap and water (tetanus booster ad hoc)
Infiltrate rabies immune globulin (20 IU/kg) into and around the margin of the bites
Administer vaccine on days 0,3,7,14, and 28

34. POSTEXPOSURE PROPHYLAXIS
Urgency rather than emergency, per se
Depends in part upon the animal species, exposure details, rapidity of diagnostic testing, and epidemiology of rabies in the local area
Consultation with knowledgeable public health officials should be routine

35. POST-EXPOSURE PROPHYLAXIS
CLEAN WOUND
Include soap and water, alcohol or benzyl- alkonium chloride etc. No suturing.
STATE HEALTH DEPARTMENT
determine risk, examine animal (if available)
VACCINATION
Human Diploid Cell Vaccine
fetal rhesus lung cell vaccine
Purified Chicken Embryo Cell vaccine
HUMAN RABIES IMMUNE GLOBULIN
HRIG
infiltrate up to half around wound, rest IM
CDC web site 2005:
Public health cost US ~$300,000,000 per year (includes cost of animal vaccination, monitoring, post-exposure prophylaxis etc.)
Approx 40,000 courses of post-exposure prophylaxis given per year in US, at a cost of ~$1000 per course of treatment.

36. RABIES IMMUNE GLOBULIN
Two Human Rabies Immune Globulins in the USA:
HyperRabTM S/D
Imogam® Rabies-HT
Both supplied in vials at ~ 150 IU/ml

37. ADVERSE REACTIONS
PEP should not be interrupted because of local or mild systemic adverse reactions
Use of anti-inflammatory, antihistaminic, and antipyretic agents suggested
Serious systemic, anaphylactic, or neuroparalytic reactions are rare