Gregory J. Martin MD Tropical Medicine – Infectious Diseases

Office of Medical Services, US Department of State Washington, DC

Animal Bites and Rabies

Disclosures These are my personal recommendations and are not

the official views of the Office of Medical Services or the Department of State

I have no financial relationship to disclose

There are non FDA approved recs for use of antibiotics and other drugs

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Goals for this lecture As worldwide deployable you will

encounter bizarre situations where YOU are the “expert” Review of some of the basics for

animal bite care

Focus on rabies as the most serious of the complications Rabies vaccine and immunoglobulin

Dispel some of the common misconceptions that have become conventional wisdom but may actually be dangerous

“We’ll have to clean that out immediately… there’s nothing dirtier than a lawyer bite”

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What bites? Mosquitoes, Snakes, Dogs, Cats, Monkeys…

Only mammals in this lecture

Dog bites annually: Tens of millions worldwide 4.5 million in the US

Highest among 5-9 yo children 885,000 seek care 30,000 reconstructive surgery 3-18% become infected 10-20 fatalities

Low income countries with dogs 76-94% of bite injuries

Rabid dogs cause the majority of rabies deaths

Cat bites annually: Worldwide 2-50% of animal

bites 400,000 in the US

66,000 ER visits

Monkey bites annually: 2-21% of animal bites 2nd to dogs in many areas Important risk for travelers

who may be unaware of how to react to monkeys

From the WHO: http://www.who.int/mediacentre/factsheets/fs373/en/ 4

Management of bite wounds

Stop significant bleeding with pressure Wound cleaning:

- In the field: use freshest water available - In the clinic/ER: cleanse surface with soap or povidine or chlorhexidine Copious NaCl irrigation of deeper wound areas with low pressure

irrigation Remove devitalized tissue Anesthetize if necessary to explore wound for debris, other injury Consider radiographs if foreign body suspected DO NOT irrigate with H2O2 as it may damage healthy tissues

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Management of bite wounds Puncture wounds:

Most likely to become infected No wound treatment significantly

decreases infections Remove foreign bodies (i.e. tooth

tip) and devitalized tissue is critical Superficial irrigation, (NOT high

pressure) into puncture site Some rec 15 mins soak in antiseptic

solution - little supporting evidence Open lacs from dog bites are safer

to close than cat or human bites.

Primary closure of open bite wounds: Less than 12 hours old

<24h for facial wounds Not on the hand or foot Clinically does not appear

infected NOT Cat or human bites,

(except to the face)

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Bacterial infections post primary bite closure Two studies: 96 patients with 169 dog bite wounds, after debridement and

thorough irrigation. Randomized to: 92 closed and 77 left open prophylactic antibiotics not given 13 developed infection; the rate did not differ whether wound was

sutured or remained open (7.6 versus 7.8 percent). Hand wounds more likely to become infected

Wound infection in 145 bites that were closed primarily: 88 bites by dogs, 45 by cats, and 12 by humans. 57% were on the head and neck. Eight patients (5.5%) developed infection despite having received

antibiotics at a mean of two hours post-injury 5 dog, 2 cat, 1 human bite infections

Maimaris et al. Dog-bite lacerations: a controlled trial of primary wound closure. Arch Emerg Med. 1988;5(3):156 Chen et al. Primary closure of mammalian bites. Acad Emerg Med. 2000;7(2):157

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Delayed primary closure

Leave bite wounds open for drainage and possible delayed primary closure 72 hours after the injury. Wound cleansing and debridement of devitalized tissue should still occur

during initial care wound should be dressed with wet saline dressings twice daily until

closure is performed.

Surgical consultation indicated for the following wounds: Deep wounds that penetrate bone, tendons, joints, or other major

structures Complex facial lacerations Wounds associated with neurovascular compromise Wounds with complex infections (eg, abscess formation,

osteomyelitis, or joint infection 8

Antibiotic prophylaxis When is it appropriate?

Routine antibiotic prophylaxis is not recommended Prophylactic antibiotics reduce infections due to some bites,

especially cat bites (80% cat bites vs 5% dogs). Antibx for 3-5 days are warranted in certain high-risk wounds:

Deep puncture wounds (especially due to cat bites) Moderate to severe wounds with associated crush injury Wounds in areas of underlying venous and/or lymphatic compromise Wounds on the hand, genitalia, face, or in close proximity to a bone or

joint (particularly the hand and prosthetic joints) Wounds requiring closure Bite wounds in compromised hosts (eg, immunocompromised, absent

spleen or splenic dysfunction or DM

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Stevens et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the IDSA. ClinInfectDis 2014:first published online 18June2014 doi:10.1093/cid/ciu296

Recommended antibiotics after an animal bite

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Antibiotic choice for bites when indicated

Cat and human bites, especially punctures, are highest risk

Consider coverage of Pasteurella, viridans strep, Fusobacterium, Capnocytophaga, Staph aureus, Bacteroides, corynebacteria, Eikenella

For most bites amox/clav 875/125 bid is the best empiric therapy For penicillin allergic: Cefuroxime, clindamycin, doxycycline, TMP/SMX or

moxifloxacin

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Consider rabies prophylaxis!

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Rabies and the “Rabies-like” lyssaviruses most may occasionally cause a rabies like illness in humans

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Lyssaviruses are associated with bats Only rabies is found in the Americas

Banyard et al. Lyssaviruses and Bats: Emergence and Zoonotic Threat. Viruses 2014, 6, 2974-2990 14

Rhabdoviridae Morphologic Characteristics

bullet shaped single stranded RNA viruses 75 ηm diameter and 150-180 ηm long

http://viralzone.expasy.org/all_by_species/22.html 15

Rhabdoviridae Growth Characteristics and Life Cycle

Affinity for brain and mucous secreting glandular tissues highly selective for neuron

groups → host transmission

Propagates in CNS of mammals, cell culture systems and embryonated bird eggs

Inactivated by sunlight, UV, air, heat, mercury, formalin and Hi/lo pH

Resistant to putrefaction in neural tissue glycerol preserves infectivity

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Rabies Epidemiology

Human Rabies cases 2004 from: Dogs Vampire Bats

Schneider, M.C. Epidemiologic Situation of Human Rabies in Latin America in 2004 WHO Epidemiological Bulletin, Vol. 30 No. 1, March 2009 WHO-RABNET http://apps.who.int/globalatlas/default.asp

Worldwide incidence ~50-60,000 human cases reported to WHO per year

95% of human cases are in Africa and Asia and ~½ in children <15 Indian subcontinent with >30,000 cases/year 1596 autopsies in Columbia in the 80s: 1.7% with undx rabies Since 1983 annual cases have decreased >90% in dogs (16000 to 1100)

and humans (355 to 35) in the Americas cases from bats have increased

>15 million human post-exposure treatments annually 5 million in China 1 million in India 40 thousand in North America ? In South America

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Tropics: >95% of rabies cases in domestic animals dogs>>cats>cattle

Temperate (US as an example): 6,154 reported cases were a decrease among all wild animals. They accounted for 92% of reported cases of US rabies in 2010. Raccoons - 36.5% Skunks - 23.5% bats - 23.2% foxes -7.0% other wild animals, including rodents and lagomorphs- 1.8% Of domestic animals cat rabies cases exceeded dogs

Rabies in Animals

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Vampire bats

Diphylla ecaudata Diaemus youngi (very rare) Desmodus rotundus (most common)

•Three species but Desmodus rotundus is currently associated with rabies

•Tropical and subtropical Americas and Caribbean

•No higher than 2000m over sea level •Temperate temperatures never lower than 150C and at least 45% humidity

Gross natural distribution of vampire bats

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Vampire Bat Associated Human Rabies

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Desmodus lands on the ground and crawls onto its prey

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Vampire bats require a blood meal at least every few days and will often revisit the same animal and same wound site repeatedly.

If unsuccessful in obtaining a meal other bats may regurgitate blood in a mouth to mouth transfer.

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Vampire bat bite

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Health impact and economic losses

• Acha published the economic impact of paralytic bovine rabies in the Americas for 1967: - >500,000 cattle deaths with an economic loss ~ US$50 million (40 years ago!) - 1990 data showed little change - 2010 decreases in many areas but marked increases in others

Disproportionate increase in vampire bat populations caused by an ecologic imbalance due to human activities: - Dramatic increase of livestock population, associated with the cattle industry, within vampire bat natural habitats - Abundant and almost unlimited source of food for vampire bats - 234 cases of human rabies associated with wildlife have occurred in Latin America 1990-2003

according to PAHO. - 175 human cases caused by vampire bats

- 95% decrease in human rabies in the Americas since 1980 PN Acha. Epidemiology of paralytic bovine Rabies and bat Rabies. Bull. Off. int. Epiz., 1967, 67, 343-382.

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Cost of Rabies Prevention US Stats

$300 million to $1 billion annually in the US: vaccination of animals (mostly dogs) animal control programs postexposure prophylaxis (PEP) maintenance of rabies labs

~40,000 PEPs/year in the US one course of HRIG and vaccine ~$1000 cost per life saved is $10,000-100,000,000 depending on

region one rabid kitten in New Hampshire associated with 650 PEPs

at a cost of >1.5 million

CDC JUL2012: http://www.cdc.gov/rabies/location/world/index.html

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Rabies Epizooses RABIES RESERVOIRS

URBAN RABIES WILD RABIES

ENZOOTIC RABIES

ASSOCIATED WITH TERRESTRIAL CARNIVORES

SUSCEPTIBLE Dead End Hosts

Cats

VECTORS

Ferrets

Perros

Vampire bat Big brown bat Silver hair bat

Red bat Free tail bat

Mapaches

Raccoons Gray foxes

Striped skunk Spotted skunk

Arctic foxes Coyotes

Mongoose

ASSOCIATED WITH BATS

Cows Goats and Sheep

Humans and horses Pigs

Beavers and woodchucks

Raccoon dogs

Dogs

Domestic cats

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Species Compartmentalization Eight separate epizootics in the US

Maryland: 672 of 709 rabies cases in raccoons 37/709 cases spread among 5 other species

Texas: 404 of 412 rabies cases in skunks only 3 in raccoons

Monoclonal Ab analysis: 8 variant rabies strains (bat not included) Some degree of specificity of strains

DEC 2014 http://www.cdc.gov/rabies/exposure/animals/wildlife_reservoirs.html

Silver-Haired Bat

1 Raccoon strain 4 Skunk strains 2 Fox strains 1 Mongoose strain Numerous bat strains 28

Strain Specificity

Sikes study of a fox rabies strain: 100x larger inoculum to infect a skunk than a fox

i.e. foxes are more susceptible to the fox strains

skunks infected with a large inoculum from a fox rapidly progress to rabies and die prior to salivary gland infection

lower levels of viral shedding in small to moderate inoculum size shedding is sufficient to infect other foxes shedding is insufficient to infect skunks

Sikes RK. Pathogenesis of Rabies in Wildlife. Am J Vet Res 1962;23:1041-47 29

Rabies Non-Threat Animals Small rodents are rarely determined to be rabid and have

never been implicated in transmission to humans.

Blanton et al. Rabies surveillance in the United States during 2010. JAVMA 2011.239:773

Human Rabies in North America Never common, ~100 cases/year in 1900 average of 55 human cases/year 1900-1950 ~70% male; median age 26.5 years

2006-2014: 0-3 cases per year 47 US cases in the 1995-2011, most were acquired in the US: 34/47 cases: domestic bat strain, Apparent exposure with direct contact in most cases Inapparent exposure are the minority

1 vampire bat strain: Mexican immigrant with hx of a vampire bat bite

9/47 dog/coyote strain from outside the US 1 raccoon strain, 1 Fox, 1 Unknown CDC’s National Center for Zoonotic, Vector-Borne, and Enteric Diseases http://www.cdc.gov/rabies/epidemiology Blanton et al. Rabies surveillance in the United States during 2010. JAVMA 2011.239:773

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Epidemiology Peak number of rabid animals in spring Human exposures most frequent during

summer Exposures highest in children, especially

boys No racial, genetic, socioeconomic

differences in susceptibility Canada 2010: 123 rabid animals 93% wildlife especially bats, foxes and

skunks Mexico 2010: 357 rabid animals 83% cattle, 10% other livestock

Blanton et al. Rabies surveillance in the United States during 2010. JAVMA 2011.239:773 32

Transmission Bites are most common route

Small abrasions or cuts especially from infected animals teeth abrasions/wounds licked by an infected animal

Mucous membrane contact with virus including nasal mucosa (bat strains)

Corneal transplant from infected donors

Laboratory exposure to aerosols or needle sticks

Transplacental, milkborne and ingestion cases have all been documented in animals

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WHO Categories of exposures All exposures warrant immediate washing and flushing of

all bite wounds and scratches.

Category I – touching or feeding animals, licks on the skin no treatment is required

Category II - nibbling of uncovered skin, minor scratches or abrasions without bleeding, licks on broken skin immediate vaccination (CDC and DoD recs add HRIG as well)

Category III – single or multiple transdermal bites or scratches, contamination of mucous membrane with saliva from licks; exposure to bat bites or scratches immediate vaccination and administration of HRIG

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US Army Case Sep 2011

Soldier died from rabies acquired from a dog bite while deployed in Afghanistan – First case in DoD in over 30 years – Symptoms began 3 months after redeployment – DoD issued an 84 page instruction in response Public health investigation into case revealed 11 other Soldiers in unit had sustained unreported and untreated rabies risk exposures – Mostly dog bites – Several persons had more than one exposure – 10 required post-exposure prophylaxis Other than military working dogs, there are no “safe” dogs or cats when deployed. ~10% of animals tested from Afghanistan were positive

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Transmission Virus appears in saliva 1-3 days before clinical evidence of disease in most

species and strains

Some African dog strains appear to be attenuated and adapted with dogs living for years with clinically silent rabies Ethiopian dogs alive >2 y with active virus but no associated human dz

Dog urine and blood has NOT been demonstrated to have virus

Bats often have prolonged periods of infectivity Develop rabies and die Develop rabies but survive non-infectious Asx infection but continued viral shedding

Siprija et al Does Contact with Urine and Blood from a Rabid Dog Represent a Rabies Risk? CID 2003; 37:1399–1400

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Exposure Initial

symptoms Clinically Evident

Onset Coma Death

Incubation Period

Prodromal Phase

Acute Neurologic

Phase Coma Phase

potential for transmission

20-60 days (usual) Years (uncommon)

1-2 days 1-2 days 1-7 days (Prolonged if

ventilator)

Rabies: Clinical Course

Hemachudha et al. J Neurovirology 2005 38

Pathogenesis Incubation Period

In humans typically 1-3 months 84% within 90 days but 1% > 1 year May be as short as 4 days Case documented 19.5 years post exposure Shorter period: in bites to the face/neck younger patients multiple bites with high viral dose

During incubation clinically silent no detectable antibody

Fishbein NEJM 329(22):1632-1638, 1993 39

Pathogenesis Incubation Period

After bite occurs: virus localized in wound area probable replication in local myocytes latent period from days to years followed by spread along

neurons to CNS possibly shortened with stress, steroids, etc

After CNS infection, rapid spread salivary glands infected shortly after CNS antibodies in serum and CSF 1-2 days prior to clinical rabies

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Pathogenesis Prodromal Period

Generally lasts 2-10 days

Numerous non-specific sx before gradual progression to acute neurologic period: pain and paresthesia at bite site in ~1/2 intense pruritus at bite site in >40% malaise, fatigue, HA, anorexia and fever apprehension, anxiety, insomnia, depression

Marked excoriation that occurred in the prodromal period before development of furious rabies

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Pathogenesis Acute Neurologic Period

Onset with development of objective signs of CNS involvement typical duration 2-7 days

Two clinical states: Furious (classical or agitated rabies) ~80% Paralytic or “dumb” rabies ~20%

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Furious Rabies Characteristics hydrophobia is pathognomonic violent, spastic contractions of the diaphragm

and accessory muscles triggered by attempts to swallow

fever 100-104o

muscle spasms, seizures, hallucinations

alternate between sx and long asx periods during which patient is alert and appropriate

death due to cardiac or pulmonary arrest

progressive neuro deterioration over 2-7 days to coma

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Paralytic Rabies Characteristics 20% of cases: especially with bat strains post exposure to nerve tissue

vaccine post corneal transplant from

patients who died of undiagnosed paralytic rabies

diagnostic dilemma

“la rage tranquille” with no agitated stage or hydrophobia 46

Coma Stage Usually occurs 4-10 days after onset of sx and

gradually develops from acute neurologic stage

Hydrophobia disappears and swallowing becomes possible

Patient may appear to be improving

anxiety and excitement replaced by: apathy stupor coma

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Diagnosis of Rabies

No technique for dx prior to CNS infection

Virus does not stimulate Ab production while immunologically protected at bite site

Ab production begins after CNS infection: rabies serum neutralizing Ab not detected until 6th day of

illness CSF Ab neg as long as 7 days after detection of serum Ab if no post exposure prophylaxis, 50% Ab by day 8 and 100%

by day 15 of clinical dz steroids or interferon may delay Ab development

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Rabies Laboratory Diagnosis

Direct fluorescent antibody (dFA) staining of full thickness punch bx from the neck above the hairline is most rapid, reliable and readily available. dFA can also be performed from a brain biopsy

Rapid Fluorescent Focus Inhibition Test (RFFIT) – WHO gold standard in vitro cell cx that measures neutralizing Ab highly sensitive and specific rare reports of an unimmunized human with Ab follow titers, only clinical rabies >50 IU

PCR is rapidly becoming available in many state labs for dx. Can be performed on saliva, CSF or biopsy material.

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1. Saliva: Collect with a dropper and place in small sterile container. Tracheal aspirates & sputa not suitable RT/PCR isolation of infectious virus in cell culture.

2. Neck biopsy: section of skin 5-6 mm in diameter from posterior region of the neck at

the hairline. minimum of 10 hair follicles sufficient depth to include cutaneous nerves at base of the follicle specimen on a piece of sterile gauze moistened with sterile water RT/PCR and IF staining for viral Ag in frozen sections of the biopsy.

3 & 4. Serum and CSF: >0.5 ml of serum and CSF; NOT whole blood

If no vaccine or RIG given, presence of serum rabies Ab makes dx and CSF tests unnecessary

Ab to rabies virus in CSF, regardless of immunization hx, suggests rabies infection.

tests for Ab include indirect IF and virus neutralization.

Diagnostic Specimens Four sample sites required by CDC to R/O Rabies

CDC Rabies Lab Request Form: www.cdc.gov/rabies/docs/standard_dfa_protocol_rabies.pdf 50

Diagnostic Specimens Do not use preservatives!

Brain biopsy. The rarity of rabies and the lack of an effective treatment make the collection of a brain biopsy unwarranted; samples negative for HSV encephalitis should be tested for rabies biopsy in a sterile sealed container RT/PCR and IF staining for viral Ag in touch impressions Suspension of brain tissue inoculated intracerebrally into mice or cell cx

confirms dx

Postmortem diagnosis by IF staining of viral Ag in touch impressions of brain tissue. Portions of medulla, cerebellum, and hippocampus- freeze and ship on dry ice Preservation of tissues by fixation in formalin is not recommended for rabies dx Immunohistochemistry (IHC) can be performed on formalin fixed tissue

patients dying after a prolonged course may not have measurable virus or Ag due to intense Ab response

Rabies specimen submission form: www.cdc.gov/rabies/docs/ror_form.pdf

Neuron with red stain indicates areas of rabies viral antigen by using IHC or avidin-biotin complex (ABC) technique.

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Pathology Histopathology

Mononuclear infiltration Perivascular cuffing of lymphocytes or PMNs Lymphocytic foci Babes nodules consisting of glial cells varying degrees of neuronal degeneration 70-80% with pathognomonic Negri bodies

cytoplasmic inclusions, round or oblong, 2-10 µm most common in the hippocampus and

cerebellar Purkinje cells one or more may be seen in a single cell consist of viral nucleocapsid proteins can be seen with light microscopy but DFA

improves ID

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Rabies Mortality

Untreated patients usually die of respiratory arrest In ICUs duration from onset to death averages 25

days patient may survive in a coma for months respiratory complications are the most common cause

of death usual complications of ICU/ventilated patients

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Rabies Post Exposure

Prophylaxis

Wound Care is most important!! generous irrigation with saline followed

by debridement and vigorous cleaning with soap solution to depth of wound

reduces risk of rabies by 90%

povidine solution increases efficacy

vaccine failures associated with poor wound care

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Rabies Post Exposure Care Immunizations

Pasteur’s dried extract of serially infected mice and rabbit spinal cords in 1885 early success no subsequent human trials

performed prior to widespread use

Semple phenol inactivated vaccine - 1919

Live attenuated (Fleury strain) grown in eggs in 1949

Suckling mouse brain with ⇓ neuro complications (1 in 8000)

Rabies vaccination post vampire bat bite Madre de Dios, Peru 2007

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Rabies Post Exposure Care Immunizations

Duck embryo vaccine developed in 1958 safe but low potency requiring

23 injections 10-20% develop antibodies 1/3 develop skin reactions significant number of vaccine

failures

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Vaccines Many inferior vaccines available outside the US.

Often less immunogenic, poorly purified Increased association with neurologic and other side effects Failure associated with protocol breach (1 in 80,000 in developed nations)

Two β-propriolactone inactivated vaccines, each ~100% efficacious:

HDCV- Human Diploid Cell Vaccine (Imovax), infected human cell line PCEC - Purified Chick Embryo Cell (RabAvert), chicken fibroblast cell culture

if hypersensitivity to other vaccines ie frequent boosters chicken allergy does not preclude use

HRIG - Human Rabies Immune Globulin – (Imogam or HyperRab) from those prevaccinated → 3-6 weeks of passive immunity with no serum sickness

DEC 2014 http://www.cdc.gov/rabies/virus.html

Product: Imovax Rabies (HDCV for pre or post-exposure) Manufacturer: Sanofi Pasteur Year Licensed: 1980

Product: RabAvert (PCECV for pre or post-exposure) Manufacturer: Novartis Year Licensed: 1997

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Vaccine and HRIG Pre-exposure:

1.0 mL IM or 0.1 mL ID in the deltoid 3 Doses: days 0, 7 and 21 - 28, complete > 30 days before exposure risk frequent risk (veterinarians) give booster q 2 years continuous, high risk (rabies lab workers) check Ab q 6 m. Average DoS/DoD traveler needs NO ADDITIONAL BOOSTERS or Ab checks.

Postexposure: CLEAN the wound and give tetanus booster if pre-immunized: 2 doses 1.0 mL deltoid IM on days 0 and 3. No HRIG! if unimmunized: 4 doses (ACIP changed 2009)

20 IU/kg HRIG, as much as possible around the bite site, remainder away from vaccination site (may give up to 7 days after 1st vaccine, later should not be used)

1.0 cc vaccine deltoid IM on days 0,3,7 and 14 (day 21-28 dropped) If immunocompromised or taking antimalarials then 5 doses still rec

Side Effects: Injection site swelling and pain, itching, HA, myalgias and fever may occur.

lmmune complex reactions occur 2-21 days late in 6% HDCV and 1% PCEC booster patients

Rupprecht et al. Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies Recommendations of the Advisory Committee on Immunization Practices. MMWR 2010:55 RR2 60

Rabies immunization Schedule One of the most common vaccine queries to MED is

regarding rabies PreExposure immunization schedule Some basics to remember:

Immunocompetent individuals uniformly have an excellent antibody response after 2 doses of rabies vaccine 3rd dose both ensures this as well as prolongs antibody response

Those who are not at very high risk (rabies lab/veterinarians) only need one PreExposure series during their lifetime No need to boost or check titers even decades after a documented

series Those with the European lower dosage repeat dose q 5 years

It is acceptable to have administration of preexposure rabies over a longer duration but NOT shorter (ideally 0, 7, 21-28d) Day 0, 14, 320 is okay Day 0, 3, 7 is not Most commonly patient gets day 0 and 7 and then shows up at health unit 6

months later without the 3rd dose. It is acceptable to give it up to year out. 61

Summary of Rabies Prevention

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Travelers and Rabies Vaccine not indicated for travelers unless staying in rural

areas for >4 weeks or with no access to medical attention 6.8% of street dogs in Thailand are rabid a dog lick was experienced by 8.9% and a dog bite by 1.3%

of travelers visiting for avg of 17 days

pre-exposure vaccine for military unit not necessary if ready access to vaccine in the event of exposure

Sailors befriend a Laotian dog 64

Bats in the Attic – Bats in the Bedroom!

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Bats in the Bedroom What do you do?

55 US/Canadian bat associated cases of human rabies (1950-2007): 22 (39%) cases a bite was reported 9 (16%) cases apparent contact but no bite

detected 6 (11%) cases bats in the home but no

known contact 2 (4%) in their bedroom

19 (34%) no hx any bat exposure Median incubation period 7 weeks If bat is available, send it for rabies

testing Consider PEP if bat is unavailable and

persons were unaware that a bite or direct contact occurred but only 2 cases in 20 years Number needed to treat and cost benefit

analysis ???? De Serres et al. Bat Rabies in the US and Canada CID 2008:46

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Recovery from Rabies

Most uniformly fatal infection in humans ~10 well documented cases of survival in proven rabies three received post exposure prophylaxis prior to

development of clinical rabies three made full recovery after intensive tx one survived with significant neurologic sequelae 6 treated with “coma therapy” and survived with

minimal neurologic sequelae Some received at least one dose of vaccine prior to symptoms

Jackson. Mgt of rabies in humans. CID 2003;36:60–3 www.cdc.gov/rabies/docs/management.pdf

Porras. Recovery from Rabies in Man. Ann Intern Med 1976;85:44-49 67

A rabies survivor – the “Milwaukee protocol” Rationale:

Marked autonomic dysfunction in acute rabies may kill the patient Rabies confers little viral or immune mediated cytopathic effects A natural immune response is sufficient to clear the virus Tetrahydrobiopterin (BH4) deficiency and cerebral vasospasm may

impact rabies mortality

Four principles: Prolonged therapeutic coma to prevent severe dysautonomia Antiviral therapy Avoidance of immune prophylaxis Prophylaxis, monitoring and tx of cerebral vasospasm

Generally not recommended unless case diagnosed very early in illness and/or some doses of vaccine given prior to symptom onset

Willoughby. Survival after Treatment of Rabies with Induction of Coma. NEJM 2005; 352 (24): 2508

Aramburo. Failure of the Milwaukee Protocol in a Child with Rabies. Clin Infect Dis 2011;53 (6): 572

The “Milwaukee Protocol” Not as promising as once hoped

Used 41 additional times with 6 additional survivors Some had received some doses of post exposure immunization Increasing evidence that some people may have an asx infection

and survive with antibodies. 10% with antibodies in one study in Peru

Modified from original case in 2004 to version 3.1 Ribavirin may delay Ab response and was dropped

Amantadine po remains although of ? value

Management of cerebral vasospasm does not appear to make a significant difference in brain injury but is still included BH4, milrinone and L-arginine

Brazilian boy had partial PEP and initial case had Ab at one week (early) so PEP may not increase pathology RIG may help in the heart and other organs where rabies found

Aramburo et al. Failure of the Milwaukee Protocol in a Child with Rabies. Clin Infect Dis 2011;53:572–4 Gilbert et al. Evidence of Rabies Virus Exposure among Humans in the Peruvian Amazon. AJTMH 2012; 87:206-215

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Rabies Treatment No effective therapy for clinical rabies

High doses of immune globulin after disease onset are ineffective

Vaccine post onset of dz may induce increased CNS pathology

Steroids blunt immune response and hasten time to death in animal models

Interferon trials in animals were promising but had no benefit in humans

Ribavirin ineffective in animal trials

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Therapy Supportive therapy

Patient isolated to minimize exposure of staff to virus in secretions and urine

virus has NOT been isolated from blood masks, gloves and gowns recommended for staff and visitors pre or post exposure prophylaxis is not required for staff or family

unless clearly contaminated

Patient should be made comfortable: barbiturates, phenothiazines and benzodiazepines used

symptomatically Use of “coma Therapy” as in in the Wisconsin survivor is worth

trying morphine is CONTRAINDICATED, even small doses markedly

increase agitation 71

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Rabies Information CDC Website: www.cdc.gov/ncidod/dvrd/rabies CDC Rabies Lab: (404) 639-1050 MartinGJ@state.gov

Thanks for your attention

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A Few TST Clarifications A person who has had a “positive” TST may receive

future TSTs Depends on the degree of positivity and the clinical

setting Once diagnosed as “LTBI” there is generally not an

indication to continue serial testing In someone diagnosed with LTBI in the distant past (>5

years) who now comes in for counselling it may be reasonable to replant a TST unless there was marked positivity in the past

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Marking the site of the TST Most important to mark the general area just so you

are not confused by an insect bite or other trauma Measurement of the planted site weal is not

necessary unless there was extravasation of a PPD after placement

Something didn’t go right Low threshold to just repeat the TST Yes there may be some boosting but remember the

boosted result is considered the “correct” result

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