Rabies Post-Exposure Prophylaxis
Lyssavirus zoonosis transmitted via mammalian bites; near-100% fatal once symptomatic — post-exposure prophylaxis with vaccine and HRIG is highly effective.
Also known as: rabies, rabies PEP, post-exposure prophylaxis, hydrophobia, lyssavirus
Overview
Acute viral encephalomyelitis caused by Lyssavirus (Rabies virus), an enveloped negative-sense RNA virus of the Rhabdoviridae family, transmitted by infected mammalian saliva (bite, less often mucous membrane exposure). Once symptomatic, mortality is virtually 100%.
Epidemiology
US: 1-3 human cases annually, mostly bat-related. Worldwide ~59,000 deaths/year, predominantly dog bites in Asia and Africa. In the US, wildlife reservoirs are bats, raccoons, skunks, foxes; small rodents (squirrels, mice) are virtually never infected.
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Risk factors
- Bite from bat, raccoon, skunk, fox, coyote, or unvaccinated dog/cat (especially abroad)
- Sleeping in a room where a bat is found (potential unrecognized exposure)
- Travel to dog-rabies endemic areas (India, China, Africa)
- Spelunking, wildlife handling, veterinary work
- Failure to seek timely PEP after exposure
Pathophysiology
Virus replicates locally in muscle, then enters peripheral nerves at neuromuscular junctions and travels retrograde axonally to the CNS at ~12-100 mm/day. Replicates massively in CNS neurons (Negri bodies on histology) → encephalitis. Then spreads centrifugally to salivary glands, skin, cornea, and other organs. Long incubation (typically 1-3 months, range days to years) reflects time required for axonal transport from the bite site.
Clinical presentation
Symptoms
- Prodrome (1-7 days): fever, malaise, headache, anorexia; pain or paresthesias at bite site (pathognomonic)
- Furious form (~80%): hydrophobia (painful pharyngeal spasms triggered by attempts to drink), aerophobia, agitation, hyperactivity, hallucinations, autonomic instability (hypersalivation, sweating, lacrimation), seizures
- Paralytic form (~20%): ascending flaccid paralysis resembling Guillain-Barre
- Coma, multi-organ failure, death within 1-2 weeks of symptom onset
Signs / physical exam
- Hypersalivation, lacrimation, sweating
- Pharyngeal/laryngeal spasm with drinking
- Hyperactivity alternating with lucid intervals
- Cranial nerve palsies
- Negri bodies (eosinophilic cytoplasmic inclusions in neurons) on autopsy — historical hallmark
Classic findings
Hydrophobia and aerophobia in an encephalopathic patient with a remote animal bite — virtually pathognomonic for clinical rabies.
Differential diagnosis
- Viral encephalitis (HSV, arboviral) — Fever, altered mental status; CSF, PCR; treat empiric acyclovir
- Guillain-Barre syndrome — Ascending flaccid paralysis, areflexia, albuminocytologic dissociation; can resemble paralytic rabies
- Tetanus — Rigidity with preserved consciousness; unattended wound; differs from rabies encephalitis
- Acute psychosis or substance intoxication — May mimic furious rabies; toxicology screen, history
- Other encephalitides (autoimmune, anti-NMDA) — Autoantibodies, immunotherapy response
Diagnostic workup
Diagnostic criteria
Clinical syndrome with exposure history and laboratory confirmation. Diagnosis is most often confirmed in the animal source.
Labs
- Pre-mortem diagnosis difficult: skin biopsy (nuchal area) with direct fluorescent antibody for viral antigen, CSF/saliva PCR, serum/CSF antibody (after 7-10 days of illness)
- Animal testing: brain tissue with direct fluorescent antibody is gold standard (requires euthanasia)
- Post-mortem: brain biopsy with Negri bodies and direct fluorescent antibody
Imaging
- MRI may show abnormal signal in brainstem, hippocampus, hypothalamus — non-specific
Diagnostic algorithm
flowchart TD
A[Potential rabies exposure<br/>bite or saliva to wound/mucosa] --> B{Animal type}
B -->|Small rodent / rabbit| C[PEP rarely indicated]
B -->|Healthy dog/cat available| D[Quarantine animal 10 days]
D -->|Healthy at 10 d| E[No PEP]
D -->|Develops illness| F[Initiate PEP]
B -->|Wild reservoir<br/>bat, raccoon, skunk, fox| G[Initiate PEP immediately<br/>test animal if available]
G --> H[Step 1: Wash wound<br/>15 min soap and water]
H --> I[Step 2: HRIG 20 IU/kg<br/>infiltrate around wound]
I --> J[Step 3: Vaccine days 0, 3, 7, 14<br/>5 doses if immunocompromised]Treatment
First-line
- Post-exposure prophylaxis (PEP) is highly effective if started promptly:
- 1. Wound care: thorough washing with soap and water for 15 minutes, then povidone-iodine or virucidal agent — reduces local viral load and is the single most important step
- 2. Human rabies immune globulin (HRIG) 20 IU/kg — infiltrate as much as possible AROUND the wound; remainder IM at a distant site. Given only ONCE, ideally on day 0
- 3. Rabies vaccine series (HDCV or PCECV) IM in the deltoid (or anterolateral thigh in young children) on days 0, 3, 7, and 14 (4 doses for immunocompetent — ACIP 2010)
- 4. Immunocompromised patients: 5-dose series on days 0, 3, 7, 14, and 28 PLUS HRIG
- 5. Pre-existing immunization (pre-exposure prophylaxis received): 2 booster doses on days 0 and 3; do NOT give HRIG
Second-line / adjunct
- Pre-exposure prophylaxis (PrEP): vaccine series for high-risk workers (veterinarians, lab workers, spelunkers, travelers to endemic areas) — 2-dose series on days 0 and 7 per ACIP 2022 update
- Milwaukee protocol (induced coma, antivirals) — experimental, virtually no proven survival benefit; not standard
- Once symptomatic, treatment is supportive comfort care; survival reports remain anecdotal
Complications
- Death from rabies encephalitis (virtually 100% once symptomatic)
- PEP side effects: mild local reactions, low-grade fever; serum sickness rare with modern HDCV/PCECV (vs. older nerve tissue vaccines)
PANCE pearls
- Bat exposures: any potential contact with a bat (e.g., waking with bat in room, child sleeping in room with bat) is grounds for PEP unless the bat tests negative — bites can be too small to detect.
- Small rodents (squirrels, hamsters, mice, rats) and rabbits virtually never transmit rabies in the US — PEP rarely indicated.
- Healthy dog/cat that bit a human can be quarantined and observed for 10 days; if remains healthy, PEP can be deferred.
- Always wash the wound first — physical removal of virus from the wound is a critical part of PEP.
- Do NOT give HRIG in the same syringe or site as the vaccine — antibody can neutralize antigen and blunt response.
References
- ACIP 2010 — Rupprecht et al., Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies (MMWR Recommendations and Reports)
- ACIP 2022 — Updated recommendations for pre-exposure prophylaxis against rabies (MMWR)
- WHO 2018 — WHO Expert Consultation on Rabies, third report (Technical Report Series 1012)
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