225.1 🎓 醫孞生版

225.1.0.1 📌 䞀頁重點

225.1.0.1.1 Rabies
  • Virus: ssRNA bullet-shaped Rhabdoviridae; Lyssavirus genus
  • Reservoir: warm-blooded mammals; primary global concern dogs (95% human cases globally)
  • Regional reservoirs:
    • Africa + Asia: dogs (largest burden)
    • Americas: bats (USA primary), raccoons, skunks, foxes, dogs (S America)
    • Europe: foxes (controlled mostly with oral wildlife vaccine)
    • Bats: worldwide; even species without obvious bite (skin contact)
  • Burden: ~ 59,000 human deaths/yr globally; 95% in Asia + Africa
  • Transmission:
    • Animal bite (saliva contains virus)
    • Scratch + saliva contact with broken skin
    • Mucous membrane exposure (rare)
    • Aerosol in caves with bat populations (very rare)
    • Organ/tissue transplant (4 USA cases from donor with undiagnosed rabies, 2004 incident)
  • Pathogenesis:
    • Inoculation site → muscle replication
    • Retrograde axonal transport to CNS (slow, weeks-months)
    • Reaches brainstem + cortex
    • Replication in CNS
    • Anterograde spread to salivary glands → infectious saliva
  • Incubation: 1-3 months (range 5 days - 7 years)
    • Shorter with proximal bites + head/face wounds
    • Severity of wound + viral load + species
  • Clinical:
    • Prodrome (2-10 d): fever, malaise, pain/paresthesia at wound site (pathognomonic), anxiety
    • Encephalitic (“furious”) rabies (80%): hyperexcitability, hydrophobia, aerophobia, hypersalivation, agitation, seizures, autonomic dysfunction → coma → death
    • Paralytic (“dumb”) rabies (20%): ascending flaccid paralysis (mimics GBS), longer survival
    • Coma + death: typically within 1-2 weeks of symptom onset
  • Diagnosis (Antemortem):
    • Skin biopsy nape of neck → immunofluorescent staining for viral antigen
    • CSF + saliva PCR (RT-PCR)
    • Rabies antibody titer (low sensitivity)
  • Post-Mortem:
    • Negri bodies in Purkinje cells of cerebellum + hippocampal neurons — eosinophilic cytoplasmic inclusions (pathognomonic)
    • Immunofluorescent staining of brain tissue
  • Mortality: ~ 100% after symptom onset (a few survivor reports with Milwaukee protocol — extremely rare)
  • Post-Exposure Prophylaxis (PEP) — Lifesaving:
    • Wound care: thorough wash with soap + water + virucidal (povidone-iodine)
    • HRIG (Human Rabies Immunoglobulin) 20 IU/kg — infiltrate wound + remainder IM (or all IM if not feasible)
    • Rabies vaccine 4-dose schedule (HDCV or PCEC): Days 0, 3, 7, 14 (immunocompromise add Day 28)
    • Together: essentially 100% effective if given before symptoms
  • Pre-Exposure Prophylaxis (PrEP): 3-dose vaccine for high-risk (veterinarian, animal handler, traveler to endemic areas, lab worker) — Days 0, 7, 21 or 28
  • Vaccination: cell-culture vaccines preferred (HDCV, PCEC, PVRV); neural tissue vaccines (Semple) being phased out due adverse events
225.1.0.1.2 Vesicular Stomatitis Virus
  • Rhabdoviridae, Vesiculovirus genus
  • Cattle, horse, pig disease
  • Rare mild human (febrile illness + oral ulcers)
  • Treatment: supportive
225.1.0.1.3 Mokola Virus
  • Africa, Lyssavirus
  • Rare human cases (encephalitis)
  • Bats + rodents
225.1.0.1.4 Australian Bat Lyssavirus
  • Australia bats
  • Human cases (post-bat exposure)
  • Pre-exposure prophylaxis with rabies vaccine works

225.1.0.2 1⃣ Rabies Virology

225.1.0.2.1 Structure
  • ssRNA, bullet-shaped (~ 180 nm × 75 nm)
  • 5 proteins: N, P, M, G, L
  • G protein = neutralizing antigen + vaccine target
  • Rhabdoviridae family
  • Lyssavirus genus
225.1.0.2.2 Genotypes
  • Genotype 1: rabies virus (worldwide)
  • Genotype 2-14: bat lyssaviruses (regional)
    • Australian bat lyssavirus (genotype 7)
    • European bat lyssavirus (genotypes 5, 6)
    • Lagos bat lyssavirus (genotype 2)
    • Mokola virus (genotype 3)
225.1.0.2.3 Pathogenesis
225.1.0.2.3.1 Stage 1: Inoculation + Local Replication
  • Virus deposited in muscle tissue
  • Replication in muscle cells (slow)
  • Eventually enters peripheral nerve endings
225.1.0.2.3.2 Stage 2: Centripetal Spread to CNS
  • Retrograde axonal transport through peripheral nerves
  • Very slow (~ 1-2 mm/hour)
  • Reaches dorsal root ganglia → spinal cord → brainstem → cerebrum
  • This phase = incubation period clinically
225.1.0.2.3.3 Stage 3: CNS Replication
  • Widespread neuronal infection
  • Negri bodies form (eosinophilic cytoplasmic inclusions)
  • Limbic system + hypothalamus involvement → behavioral + autonomic changes
225.1.0.2.3.4 Stage 4: Centrifugal Spread
  • Anterograde axonal transport
  • Reaches salivary glands, skin, organs
  • Infectious saliva (= transmission window for next animal)
225.1.0.2.3.5 Stage 5: Death
  • Coma + multi-organ failure
  • Usually within 1-2 weeks of symptom onset

225.1.0.3 2⃣ Epidemiology

225.1.0.3.1 Global Distribution
  • ~ 59,000 human deaths/yr (WHO estimates; possibly underreported)
  • 95% in Asia + Africa
  • India alone: 35% of global cases
  • China + SE Asia + sub-Saharan Africa significant
  • USA: 1-3 human deaths/yr (mostly bat exposure)
  • Australia: rare (Australian bat lyssavirus)
  • Antarctica: rabies-free
225.1.0.3.2 Reservoir + Vectors
225.1.0.3.2.1 Domestic Dogs (Asia + Africa)
  • Major source globally
  • 95% human cases from dog bites
  • Mass dog vaccination = primary public health strategy
  • WHO + OIE 2030 elimination of dog-mediated rabies goal
225.1.0.3.2.2 Bats (USA + Australia + Globally)
  • USA primary reservoir
  • Even species that don’t bite (skin contact) can transmit (saliva)
  • Insectivorous bats most common
  • Bats in homes (especially bedrooms) → recommend PEP even without identified bite
225.1.0.3.2.3 Wild Carnivores
  • Raccoons (USA Northeast)
  • Skunks (USA Central + West)
  • Foxes (Europe; controlled by oral wildlife vaccine baits)
  • Coyotes (USA Texas)
  • Mongoose (Caribbean, India)
  • Jackals (Asia)
225.1.0.3.2.4 Other Animals
  • Cats: spread from animals
  • Small rodents (mice, rats, squirrels) — NOT typically rabid (don’t survive infection)
  • Pet ferrets, rabbits — rare
  • Cattle, horses — can be infected, usually not source

225.1.0.4 3⃣ Clinical

225.1.0.4.1 Incubation Period
  • 1-3 months typical (range 5 days to > 7 years)
  • Shorter with:
    • Proximal bites (face, scalp, head, neck — closer to CNS)
    • Severe wounds
    • High viral inoculum
    • Specific virus genotype
225.1.0.4.2 Prodromal Phase (2-10 Days)
  • Fever, malaise
  • Pain or paresthesia at wound site (pathognomonic clue — even healed)
  • Anxiety, irritability
  • Nausea
  • Sore throat
225.1.0.4.3 Acute Neurologic Phase
225.1.0.4.3.1 Encephalitic (“Furious”) Rabies — 80%
  • Hyperexcitability + hyperactivity
  • Hydrophobia (drinking attempts → painful pharyngeal spasm; pathognomonic)
  • Aerophobia (puff of air → spasm)
  • Hypersalivation (“foaming at mouth”)
  • Agitation, restlessness
  • Hyperthermia
  • Autonomic dysfunction: arrhythmia, BP swings, papilledema
  • Hallucinations
  • Seizures
  • Lucid intervals between agitation
  • Progresses to coma
225.1.0.4.3.2 Paralytic (“Dumb”) Rabies — 20%
  • Ascending flaccid paralysis
  • Mimics GBS
  • Onset at site of wound
  • Loss of reflexes
  • Longer survival (weeks)
  • No hydrophobia / aerophobia typically
225.1.0.4.4 Coma + Death
  • 1-2 weeks after symptom onset
  • Respiratory + cardiac failure
  • Multi-organ failure
  • Some prolong survival with ICU support but recovery extremely rare
225.1.0.4.5 Survival Reports — Milwaukee Protocol
  • 2004 Jeanna Giese case (Wisconsin) — first documented survivor without prior vaccination
  • Milwaukee Protocol: induced coma + ketamine + supportive
  • ~ 30 attempts globally; ~ 5 documented survivors
  • 2024 controversies: protocol effectiveness questioned; some now disfavor
  • Most patients still die despite protocol

225.1.0.5 4⃣ Diagnosis

225.1.0.5.1 Antemortem
225.1.0.5.1.1 Skin Biopsy Nape of Neck
  • Hair follicle innervation by sensory neurons containing virus
  • Immunofluorescent staining for viral antigen
  • Sensitivity 50-70%
225.1.0.5.1.2 CSF + Saliva PCR (RT-PCR)
  • Sensitive in symptomatic phase
  • Repeat samples increase sensitivity
225.1.0.5.1.3 Serum + CSF Rabies Antibody Titer
  • Low sensitivity in unvaccinated patients
  • Useful in distinguishing from vaccine response
225.1.0.5.2 Postmortem
  • Negri bodies in Purkinje cells of cerebellum + hippocampal neurons + medulla
  • Eosinophilic cytoplasmic inclusions (pathognomonic)
  • Immunofluorescent antigen staining of brain tissue
  • PCR of brain tissue
225.1.0.5.3 Animal Testing
  • Suspected animal: humane euthanasia + brain testing
  • Direct Fluorescent Antibody (DFA) staining of brain tissue (gold standard for animal rabies)
  • 1-2 day result
225.1.0.5.4 Differential
  • Tetanus (different muscle spasm pattern, no hydrophobia)
  • Encephalitis (other causes)
  • Atypical GBS
  • Psychiatric (consider after rule out organic)
  • Strychnine poisoning

225.1.0.6 5⃣ Treatment

225.1.0.6.1 Once Symptomatic: Almost Always Fatal
  • Aggressive supportive care
  • ICU
  • Milwaukee Protocol attempted in rare cases (controversial 2024)
  • Palliative care
225.1.0.6.2 Prevention Is Everything

225.1.0.7 6⃣ Post-Exposure Prophylaxis (PEP)

225.1.0.7.1 Triage After Exposure
225.1.0.7.1.1 Was There an Exposure?
  • Bite, scratch, saliva contact with broken skin or mucous membrane
  • Bat bite/scratch (even without obvious mark — bat in home)
  • Solid organ transplant from donor with undiagnosed rabies
225.1.0.7.1.2 Animal Risk Assessment
  • Domesticated dog/cat/ferret:
    • Observe 10 days if available — if remains healthy, no rabies
    • If develops symptoms → euthanize + test
    • Vaccinated animal lower risk
  • Wild carnivores (bat, raccoon, skunk, fox, coyote): assume rabid; PEP immediately
  • Stray, unknown vaccination: PEP
  • Small rodents, rabbits: usually no PEP (low risk)
  • Geographic context: imported from endemic country
225.1.0.7.2 PEP Components
225.1.0.7.2.1 1. Wound Care
  • Thorough wash with soap + water × 15 min
  • Virucidal: povidone-iodine, ethanol
  • Don’t suture wound (risk of inoculation deeper)
  • Tetanus update
225.1.0.7.2.2 2. HRIG (Human Rabies Immune Globulin)
  • 20 IU/kg total dose
  • Infiltrate around wound as much as anatomically feasible
  • Remainder IM at distant site (gluteal)
  • Within 7 days of vaccine first dose (best with first dose, but can give up to 7 days)
  • If previously vaccinated (PrEP): NO HRIG needed
225.1.0.7.2.3 3. Rabies Vaccine
  • Cell-culture vaccine (HDCV — Human Diploid Cell Vaccine; PCEC — Purified Chick Embryo Cell)
  • 4-dose schedule (USA): Days 0, 3, 7, 14
  • Immunocompromised: 5-dose schedule (add Day 28)
  • Deltoid (or anterolateral thigh in children)
225.1.0.7.3 Previously Vaccinated (PrEP)
  • 2 doses: Days 0 + 3
  • NO HRIG
225.1.0.7.4 PEP Failures
  • Extremely rare with proper administration
  • Failures typically due:
    • Delayed initiation
    • Inadequate wound care
    • Wrong vaccine (vs cell-culture)
    • Incomplete series
    • Immunocompromise

225.1.0.8 7⃣ Pre-Exposure Prophylaxis (PrEP)

225.1.0.8.1 Indications
  • Veterinarians, animal handlers
  • Laboratory workers handling rabies virus
  • Travelers to high-risk countries (especially long-term, rural, expat)
  • Bat researchers, wildlife biologists
  • Endemic country residents with significant exposure risk
225.1.0.8.2 Schedule (Updated 2022 ACIP)
  • 2-dose: Days 0 + 7 (lower risk groups)
  • 3-dose: Days 0, 7, 21 or 28 (higher risk + longer-term protection)
  • Booster based on serology + risk
225.1.0.8.3 Advantages of PrEP
  • No HRIG needed post-exposure
  • Simpler post-exposure (2 doses)
  • Critical for hard-to-reach populations + remote workers

225.1.0.9 8⃣ Animal Bite Management

225.1.0.9.1 Initial Steps
  • Wound care immediately
  • Tetanus prophylaxis
  • Antibiotic prophylaxis (amox-clavulanate covers most bite pathogens)
  • Determine rabies risk based on animal + geography
225.1.0.9.2 Rabies Risk Algorithm
  1. Domestic dog/cat/ferret bite:
    • Vaccinated + healthy + observable: 10-day observation; no PEP unless animal develops symptoms
    • Unvaccinated or unknown + observable: 10-day observation + decide on PEP based on jurisdiction
    • Stray + unobservable: start PEP
  2. Wild carnivore (raccoon, skunk, fox, bat, coyote): start PEP
  3. Small rodent / rabbit: usually no PEP
  4. Mass exposure (cave bat): PEP for all
  5. Travel to endemic country: PEP based on bite + risk
225.1.0.9.3 Special: Bat Exposure
  • PEP if bat bite/scratch
  • PEP if bat in bedroom of sleeping person / unattended child (bite may have occurred without awareness)
  • PEP if direct contact with bat (sliding, falling, etc.) and unable to rule out bite

225.1.0.10 9⃣ Prevention + Public Health

225.1.0.10.1 Dog Vaccination
  • Mass dog vaccination = key strategy
  • Sub-Saharan Africa + Asia priority
  • Decreases dog-mediated rabies dramatically
  • WHO + OIE 2030 goal: end dog-mediated rabies deaths
225.1.0.10.2 Oral Wildlife Vaccine Baits
  • Europe + USA fox/raccoon: effective
  • Air-dropped or hand-distributed baits
225.1.0.10.3 Pre-Travel Counseling
  • High-risk destinations: discuss PrEP
  • Avoid stray animal contact
  • Awareness of local rabies risk
225.1.0.10.4 Bat Awareness
  • Don’t handle bats
  • If bat in home: try to capture for testing (don’t release without testing)
  • PEP if bat in sleeping area
225.1.0.10.5 Vaccine Stockpiles
  • HRIG + cell-culture vaccines for global emergency
  • WHO stockpile
225.1.0.10.6 Surveillance
  • Active surveillance in endemic countries
  • Animal + human case reporting
  • 通報 mandatory

225.1.0.11 10. Other Rhabdoviruses

225.1.0.11.1 Vesicular Stomatitis Virus (VSV)
  • Vesiculovirus genus
  • Cattle, horse, pig vesicular disease
  • Rare mild human (febrile illness, oral vesicles, flu-like)
  • Self-limited
225.1.0.11.2 Mokola Virus
  • Lyssavirus
  • Africa
  • Rare human cases (encephalitis)
  • Bats + rodent reservoir
  • No specific treatment; rabies vaccine may not protect (different antigen)
225.1.0.11.3 European Bat Lyssaviruses (EBLV-1, EBLV-2)
  • Europe bats
  • Rare human cases
  • Rabies PEP may help
225.1.0.11.4 Australian Bat Lyssavirus
  • Australia
  • Bat reservoir
  • Human cases (rare but fatal)
  • Rabies vaccine protects (cross-protection)
225.1.0.11.5 Duvenhage Virus
  • Africa
  • Bats
  • Rare human cases