01Approach to the Critical Patient/attcp46

Immediate priorities

›Clinical rabies presentation triggers

›Hydrophobia or aerophobia

›Pathognomonic for clinical rabies

›Immediate isolation and neurology/critical care consultation

›Progressive encephalitis after animal exposure

›Agitation, confusion, hypersalivation

›Autonomic instability (tachycardia, hypertension, diaphoresis)

›Ascending paralysis pattern

›Paralytic (dumb) rabies mimics Guillain-Barre syndrome

›Bladder incontinence and myoedema favor rabies over GBS

›If clinical rabies suspected, activate infectious disease and critical care immediately

›No proven effective treatment exists once symptoms develop

›Palliative and comfort-focused planning appropriate early

PEP decision pathway

›Exposure risk stratification

›WHO Category I: touching or feeding animal, licks on intact skin

›No PEP indicated

›WHO Category II: nibbling of uncovered skin, minor scratches without bleeding

›Wound care plus vaccine only (no HRIG)

›WHO Category III: transdermal bites or scratches, licks on broken skin, mucous membrane contamination, bat exposure

›Wound care plus HRIG plus full vaccine series

›Bat found in room with sleeping person, unattended child, or intoxicated person

›Treat as Category III even without visible bite

›Time-critical actions for all exposures

›Wound irrigation with soap and water for at least 15 minutes

›Reduces rabies transmission risk by up to 50% in animal studies

›Apply virucidal agent (povidone-iodine or alcohol-based antiseptic)

02History/hx53

Exposure characterization

›Type of exposure

›Bite: penetration of skin by teeth

›Highest transmission risk

›Non-bite: scratch, mucous membrane contact, open wound contamination with saliva or neural tissue

›Lower but significant risk depending on site

›No physical contact

›Casual contact, handling intact skin: no risk

›Animal species

›Bats: most common source in the United States

›Bat bite often invisible — examine carefully

›Skunks, raccoons, foxes, coyotes: high-risk terrestrial wildlife

›Domestic dogs: predominant worldwide source

›Dogs, cats, ferrets: eligible for 10-day observation period

›Small rodents (squirrels, hamsters, rats, mice) and rabbits

›Almost never infected; have not transmitted rabies to humans in the US

›Provocation status

›Unprovoked attack more likely to involve a rabid animal

›Anatomic site

›Face, head, neck, and hands carry highest risk

›Dense innervation and proximity to CNS shortens incubation

›Time since exposure

›Incubation typically 1 to 3 months; range days to years

›PEP should be initiated immediately but effective even months after exposure

Animal and geographic context

›Animal availability

›Animal available for observation or testing

›Domestic dogs, cats, ferrets: observe for 10 days

03Physical Exam/exam38

Wound assessment

›Wound characterization

›Location, depth, and number of wounds

›Evidence of dermal penetration by teeth

›Highly innervated areas (face, hands): higher-risk bites

›Occult wound search

›Bat bites extremely small and easily missed

›Systematic full skin examination required

›Regional lymphadenopathy draining bite site

›Secondary infection signs

›Erythema, warmth, induration, purulent drainage

›Lymphangitis tracking proximal to wound

›Cellulitis extent mapping

Neurologic and systemic exam

›Vital signs in symptomatic patient

›Fever as systemic infection marker

›Tachycardia and hypertension as autonomic instability markers

›Autonomic dysfunction: diaphoresis, piloerection

›Neurologic examination

›Mental status: confusion, agitation, delirium

›Cranial nerve assessment: dysphagia, diplopia

›Motor strength: ascending weakness pattern

›Sensation: paresthesia at bite site

›Reflexes: hyperreflexia early, areflexia in paralytic form

›Classic clinical signs if rabies suspected

›Hydrophobia: laryngeal spasm triggered by attempt to drink

›Pathognomonic finding

›Aerophobia: spasm triggered by air current

04Differential Diagnosis/ddx38

Life-threatening mimics

›Viral encephalitides

›Herpes simplex encephalitis

›ICD-10 B00.4

›Temporal lobe predilection on MRI; acyclovir responsive

›Arboviral encephalitis (West Nile, Eastern equine, Nipah)

›ICD-10 A83.x

›Seasonal and geographic exposure history

›Enteroviral encephalitis

›ICD-10 A85.0

›Children predominantly affected

›Neuromuscular conditions

›Guillain-Barre syndrome

›ICD-10 G61.0

›Ascending paralysis without encephalopathy

›Paralytic rabies closely mimics; differentiated by bladder incontinence and myoedema in rabies

›Transverse myelitis

›ICD-10 G37.3

›Sensory level and bladder dysfunction

Other diagnoses to consider

›Infectious conditions

›Tetanus

›ICD-10 A35

›Trismus and muscle rigidity; may overlap with rabies presentation

›Bacterial meningitis or encephalitis

›ICD-10 G00.x / G04.x

›CSF pleocytosis; bacterial gram stain and culture

›Neuromyelitis optica spectrum disorder

05Laboratory Tests/lt35

Baseline labs for exposure management

›Routine baseline (pre-symptomatic exposure patient)

›Complete blood count

›Baseline for wound infection monitoring

›Generally nonspecific in rabies exposure

›Basic metabolic panel

›Renal function for antibiotic dosing

›Electrolyte baseline

›Liver function tests

›Baseline if systemic infection develops

Diagnostic labs for suspected clinical rabies

›CSF analysis

›Mild lymphocytic pleocytosis may be present

›Not specific; may be normal early

›Rabies virus neutralizing antibody in CSF

›Confirms diagnosis in unvaccinated patient

›Elevated protein with normal glucose typical

›Virologic testing (consult public health or CDC before ordering)

›RT-PCR on saliva

›Sensitivity approximately 70% on single sample

›Greater than 98% on serial samples

›Immunohistochemistry on nuchal skin biopsy

›4 mm punch biopsy from nape of neck with hair follicles

›Sensitivity approaches 100%

›Rabies virus neutralizing antibody: serum and CSF (RFFIT)

›Rapid fluorescent focus inhibition test

›Adequate post-vaccination response defined as 0.5 IU/mL or greater

06Diagnostic Tests/dt49

Scoring Systems

›WHO exposure category classification

›Category I: no PEP needed

›Touching or feeding animal, licks on intact skin

›Category II: vaccine only

›Nibbling uncovered skin, minor scratches without bleeding

›Category III: vaccine plus HRIG

›Transdermal bites or scratches

›Licks on broken skin or mucous membranes

›Bat exposures regardless of visible bite

›CDC/ACIP PEP decision framework

›Animal species risk tier

›High risk: bats, skunks, raccoons, foxes, coyotes

›Low risk: dogs/cats/ferrets (eligible for 10-day observation)

›Very low risk: small rodents and rabbits

›Vaccination status of biting animal

›Currently vaccinated domestic animal reduces but does not eliminate risk

›Wisconsin Rabies Algorithm for common exposure scenarios

›Available via state health department consultation

MRI

›Brain MRI in suspected clinical rabies

›T2 and FLAIR signal changes

›Brainstem involvement

›Hippocampus and hypothalamus signal abnormalities

›Deep gray matter involvement

›Typically no gadolinium enhancement

›Distinguishes rabies from many other encephalitides

›Sensitivity limited; normal MRI does not exclude rabies

07Disposition/dispo32

Discharge criteria

›Standard PEP visit (majority of presentations)

›Wound care completed

›HRIG infiltrated into and around wound (Day 0)

›First rabies vaccine dose administered

›Follow-up plan for remaining vaccine doses documented

›Doses due on Days 3, 7, and 14

›Can be given at PCP, urgent care, or ED

›Animal observation arranged if applicable (10-day period)

›Return precautions provided

›Approximately 30,000 to 60,000 patients initiate PEP annually in the US through ED

Admission indications

›Clinical rabies presentation

›Any encephalitic or paralytic features after animal exposure

›ICU level care for autonomic instability and airway management

›Severe or extensive wounds

›Surgical management required

›Complex facial or hand lacerations

›Wound-related complications

›Deep infection, abscess, necrotizing soft tissue infection

›Hemodynamic compromise from wound-related sepsis

›Social or access concerns

›Inability to ensure follow-up for vaccine series

›Consider public health facilitated outpatient plan

Follow-up requirements

›Vaccine schedule adherence

›Minor delays of a few days inconsequential

›Longer lapses: consult public health authorities

08Treatment/t67

Immediate wound care

›Irrigation protocol

›Copious soap and water irrigation for at least 15 minutes

›Reduces rabies transmission risk by up to 50%

›Most critical single intervention for wound decontamination

›Virucidal agent application

›Povidone-iodine or alcohol-based antiseptic

›Wound closure

›Avoid primary closure when possible

›Minimizes deeper tissue contamination

›If cosmetically necessary, delayed primary closure preferred

HRIG administration

›Human Rabies Immune Globulin (HRIG)

›Dose: 20 IU/kg body weight

›Infiltrate as much as anatomically feasible into and around all wounds

›Remaining volume given IM at site distant from vaccine

›Timing

›Day 0 (same day as first vaccine dose)

›Can be given up to Day 7 if initially missed

›Do NOT give after Day 7 — blunts anamnestic immune response

›Do NOT inject at same anatomic site as vaccine

›Do NOT mix in same syringe as vaccine

›Previously vaccinated patients: NO HRIG

›May blunt anamnestic immune response

Rabies vaccine

›Vaccine products available

›HDCV (Imovax Rabies): human diploid cell vaccine

›PCECV (RabAvert): purified chick embryo cell vaccine

09Special Populations/sp48

Pregnancy

›PEP safety in pregnancy

›Rabies PEP has no known contraindications in pregnancy

›Rabies is uniformly fatal; PEP always indicated after true exposure

›HRIG: pregnancy category C; benefit outweighs theoretical risk

›Rabies vaccines (HDCV, PCECV): no evidence of fetal harm

›Inactivated vaccines considered safe in all trimesters

›Wound care modifications

›Standard irrigation and debridement protocols apply

›Antibiotic selection: amoxicillin-clavulanate safe in pregnancy

›Avoid doxycycline (teratogenic in second/third trimester)

›Avoid fluoroquinolones in pregnancy

›Monitoring

›Obstetric consultation for severe or multiple wounds

›Post-vaccination serology for immunocompromised pregnant patients

Geriatric

›Immunosenescence considerations

›Elderly patients may have attenuated vaccine immune response

›Post-vaccination serology consideration in 65 and older with significant exposure

›Higher baseline immunosuppressive medication use

›Corticosteroids, disease-modifying agents: treat as immunocompromised

›Wound healing

›Increased risk of secondary wound infection

›Lower threshold for antibiotic prophylaxis

›Comorbidities affecting wound management

›Anticoagulation: bleeding risk with HRIG infiltration

›Peripheral vascular disease: impaired healing

›Falls and injury mechanism

10Background/b64

Epidemiology

›Global burden

›Approximately 59,000 deaths annually worldwide

›95% occur in Asia and Africa

›Dogs are the primary reservoir in most of Asia, Africa, and Latin America

›Rabies is classified as a neglected tropical disease

›US epidemiology

›1 to 3 human deaths per year in the US

›Bats account for most US human rabies cases

›Most cases have no recognized bat bite

›Approximately 30,000 to 60,000 PEP courses initiated annually in the US

›Most commonly through emergency departments

›All mammalian species susceptible; transmission documented in bats, dogs, raccoons, skunks, foxes, coyotes

›Small rodents and rabbits essentially never transmit rabies to humans in the US

›Reservoir species by region

›Northeastern US: raccoons predominant

›South-central US: skunks

›Western US: foxes, bats

›National: bats in all regions

Pathophysiology

›Viral characteristics

›Rabies virus: single-stranded negative-sense RNA virus

›Family Rhabdoviridae, genus Lyssavirus

›Highly neurotropic; minimal viremia

›Transmission and entry

›Entry via bite: virus in animal saliva contacts peripheral nerve endings

›Non-bite exposures: mucous membranes, open wounds with saliva contact

›Virus binds nicotinic acetylcholine receptors and neural cell adhesion molecules

11Patient Discharge Instructions/pdi36

copy discharge instructions

›What happened today

›You were treated for a potential rabies exposure

›You received wound cleaning and your first rabies vaccine shot

›You received rabies immune globulin (HRIG) to provide immediate protection

›Rabies is almost always preventable if the complete vaccine series is given

›It is nearly always fatal once symptoms appear

›Completing all vaccine doses is essential

›Your vaccine schedule

›Return for your remaining rabies vaccine doses

›Day 3 after today's visit

›Day 7 after today's visit

›Day 14 after today's visit

›These doses can be given at your family doctor, an urgent care clinic, or the emergency department

›Even a few days of delay is okay; contact public health if you miss a dose by more than a week

›Animal monitoring

›If a dog, cat, or ferret bit you, it must be watched for 10 days

›If the animal stays healthy for 10 days, your remaining vaccine doses may not be needed

›Your doctor or public health authority will let you know

›Wound care at home

›Wash the wound gently with soap and water twice daily

›Watch for signs of infection: increasing redness, swelling, warmth, pus, or red streaks

›Keep wound covered with clean bandage until healing

›Return to the emergency department immediately if you develop

›Fever or shaking chills

›Numbness, tingling, or pain at or near the bite site

›Difficulty swallowing or drinking water

›Fear of water or air currents

12References/r34

Guidelines and key sources

›ACIP 2010 reduced PEP schedule

›Rupprecht CE, Briggs D, Brown CM, et al. Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies. MMWR Recomm Rep. 2010

›Established 4-dose PEP regimen (Days 0, 3, 7, 14) as standard of care

›Annals of Emergency Medicine endorsement 2010

›ACIP 2022 pre-exposure prophylaxis update

›Rao AK, Briggs D, Moore SM, et al. Use of a Modified Preexposure Prophylaxis Vaccination Schedule. MMWR. 2022

›Updated 2-dose PrEP schedule on Days 0 and 7

›CDC Yellow Book 2025

›Wallace RM and Shlim DR. Rabies. CDC Yellow Book 2025

›Comprehensive travel and exposure guidance

›JAMA Network Open 2022

›Yuan F, Iso T, Rizk E, et al. Implementation of Clinical Decision Support on ED Delivery of HRIG. JAMA Netw Open. 2022

›Clinical decision support tool to improve HRIG delivery

›JAMA Network Open 2023

›Charniga K, Nakazawa Y, Brown J, Jeon S, Wallace RM. Risk of Rabies and Implications for PEP Administration in the US. JAMA Netw Open. 2023

Landmark studies and reviews

›Lancet Neurology 2013

›Hemachudha T, Ugolini G, Wacharapluesadee S, et al. Human Rabies: Neuropathogenesis, Diagnosis, and Management. Lancet Neurol. 2013

›Comprehensive review of pathophysiology and clinical management

›Lancet 2014

›Fooks AR, Banyard AC, Horton DL, et al. Current Status of Rabies and Prospects for Elimination. Lancet. 2014

›Lancet Infectious Diseases 2023

›Whitehouse ER, Mandra A, Bonwitt J, et al. Human Rabies Despite PEP: Systematic Review of Fatal Breakthrough Infections. Lancet Infect Dis. 2023

›Confirmed every failure involved protocol deviation

›Lancet 2025

›Kulkarni PS, Potey AV, Kapse D, et al. PEP Regimen of Rabies Monoclonal Antibody and Vaccine in Category III Exposures. Phase 4 Trial. Lancet. 2025

›Monoclonal antibody non-inferior to HRIG

Evidence & Review

Evidence & Review