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DETAILED NOTES: RABIES

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1. INTRODUCTION

• Rabies (from Latin rabere = to rage) is also called hydrophobia in humans and lyssa in animals.
• It is a fatal viral zoonotic encephalitis caused by the rabies virus.
• Nearly 100% fatal once clinical symptoms appear.
• Estimated 59,000 human deaths annually worldwide, predominantly in Asia and Africa.
• Rural populations and children are disproportionately affected - ~40% of rabid bites occur in those under 15 years of age.

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2. ETIOLOGY (Virology)

• Causative agent: Rabies virus - genus Lyssavirus, family Rhabdoviridae
• Morphology: Bullet-shaped or rod-shaped, 75 x 180 nm
• Genome: Single-stranded, negative-sense (antisense) RNA, non-segmented; ~11,932 nucleotides
• Encodes 5 proteins:
  1. Nucleocapsid (N) protein - most abundant; used for diagnosis
  2. Phosphoprotein (P)
  3. Matrix protein (M)
  4. Glycoprotein (G) - surface spikes; responsible for host cell attachment, viral entry, and virus neutralizing antibody production
  5. Large polymerase (L) protein

Serotypes / Related Lyssaviruses:

1. Classical rabies virus (genotype 1)
2. Lagos bat virus
3. Mokola virus
4. Duvenhage virus
5. European Bat Lyssavirus I (EBL I)
6. European Bat Lyssavirus II (EBL II)
7. Australian Bat Lyssavirus (ABLV)

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3. RESERVOIRS & EPIDEMIOLOGY

Reservoir Animals:

• All warm-blooded animals (including humans) are susceptible.
• Major global reservoir: Domestic dogs (responsible for 99% of human rabies deaths worldwide)
• Other reservoirs by region:
  • USA: Bats (most common source of indigenous human rabies), raccoons, skunks, foxes
  • Europe: Red foxes, bats
  • India/Asia/Africa: Dogs remain the primary reservoir
• The virus is present in the saliva of infected animals

Global Epidemiology:

• Occurs worldwide except Antarctica and some islands
• Endemic canine rabies eliminated from the USA (declared free in 2007) and most high-income countries
• India accounts for ~36% of global rabies deaths
• USA had only 5 human rabies deaths in 2021, and zero in 2019, 2020, and 2022

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4. TRANSMISSION

1. Bite of a rabid animal - most common route; virus in saliva enters wound
2. Lick on broken skin or mucous membrane (non-bite exposure)
3. Scratch with contaminated claws
4. Aerosol - rare; documented in bat-inhabited caves (Frio Cave, Texas) and laboratory accidents
5. Organ/tissue transplantation - documented cases; e.g., 2004 USA cluster where 4 recipients died after receiving organs from a donor with undiagnosed rabies
6. Corneal transplant - rare documented cases

Transmission from person-to-person is extremely rare and not documented outside transplantation.

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5. PATHOGENESIS

Step-by-Step Sequence (Human):

• Virus enters the body following bite of a rabid animal; virus-laden saliva contacts abraded skin or mucous membrane.
• The dose (concentration of virus in inoculum) and site of bite (proximity to CNS) determine incubation period.

• Virus replicates locally at the bite site in muscle cells (myocytes) for days to weeks before entering nerves.

• Virus invades peripheral nerve endings (unmyelinated sensory and motor nerve endings) and enters the cytoplasm of axons.
• Travels via retrograde axonal transport (travels up nerve from periphery to CNS) at approximately 8-20 mm/day.

• Enters the spinal cord and ascends to the brain.
• Predominantly infects neurons of the brainstem, hippocampus, cerebellum, and limbic system.
• Associated with neuronal dysfunction (there is limited actual neuron death - more functional disruption).

• Virus spreads centrifugally from brain via peripheral nerves to:
  • Salivary glands (enabling transmission)
  • Cornea, skin, heart, adrenal glands, lungs, kidneys, skeletal muscle

• Location of bite - face/neck = shorter incubation; leg = longer
• Severity and depth of bite
• Viral load (amount of virus)
• Host immune response

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6. INCUBATION PERIOD

• Usual range: 1 to 3 months (most commonly 20-90 days)
• Can range from as short as 4 days to as long as several years
• Bites to the face/head: shorter incubation (~1 month)
• Bites to the extremities: longer incubation (several months)

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7. CLINICAL FEATURES

Stages of Rabies (Table):

Two Clinical Forms:

A) Furious (Encephalitic) Rabies - 80% of cases:

• Hydrophobia - fear and spasm on attempting to swallow water (most characteristic feature); present in up to 80% of patients
• Aerophobia - fear of air drafts; spasms of pharyngeal and nuchal muscles triggered by air
• Spasms last 1 to 5 minutes, triggered by swallowing attempts, or tactile, auditory, visual, or olfactory stimuli
• Anxiety, agitation, hyperactivity, bizarre behavior
• Hallucinations, delirium, aggression
• Autonomic dysfunction: excessive salivation, lacrimation, sweating, piloerection, hyperpyrexia (fever may reach 105-107°F)
• Seizures
• As disease progresses: spasms become more frequent, then coma supervenes

B) Dumb (Paralytic) Rabies - 20% of cases:

• Ascending flaccid paralysis starting from the bitten limb, progressing to quadriparesis
• Facial paralysis
• Less agitation; no hydrophobia
• Resembles Guillain-Barré syndrome clinically
• More common with bat-acquired rabies
• Longer course but same fatal outcome

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8. DISEASE IN ANIMALS

Disease in Dogs - Two Forms:

Furious Form:

• Change in temperament (docile animal becomes aggressive)
• Excitement, restlessness, biting without provocation
• Excessive salivation, dilated pupils
• Altered bark (becomes husky/hoarse)
• Animal may bite at anything and roam widely ("mad dog")
• Later: convulsions, paralysis, and death

Dumb (Paralytic) Form:

• Less common but more dangerous (less obvious signs)
• Animal appears docile/depressed, not aggressive
• Dropped jaw, inability to bark, excessive drooling
• Ascending paralysis
• May be mistaken for a bone stuck in throat - never put your hand in a dog's mouth if this is suspected

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9. NEGRI BODIES (Pathological Hallmark)

• Intracytoplasmic, eosinophilic inclusion bodies found in neurons
• Located in the cytoplasm of infected neurons
• Most abundant in: Purkinje cells of cerebellum and hippocampal pyramidal cells (Ammon's horn)
• Represent accumulations of viral nucleocapsid protein within viral replication compartments
• Pathognomonic (diagnostic) of rabies
• Staining: Eosinophilic on H&E; also seen by Sellers' stain, Giemsa, Mann's method
• Demonstrated in brain tissue at autopsy (or biopsy)

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10. DIAGNOSIS

Antemortem (Before Death) Specimens:

1. Saliva - RT-PCR for viral RNA (most sensitive)
2. Serum - Neutralizing antibodies to rabies virus (diagnostic in previously unvaccinated)
3. CSF - Mononuclear pleocytosis; rabies-specific antibodies in CSF (diagnostic regardless of vaccination status)
4. Skin biopsy (nape of neck) - DFA (Direct Fluorescent Antibody) for viral antigen in cutaneous nerves at base of hair follicles; also RT-PCR
5. Corneal impression smears - Low yield; generally not used

Postmortem (After Death):

• Brain tissue (hippocampus, cerebellum) - DFA test; histology for Negri bodies

Key Diagnostic Tests:

CSF Findings:

• Mononuclear pleocytosis in >50% of cases in week 1, rising to 87% after week 1
• Elevated protein
• Normal glucose

MRI Findings:

• FLAIR/T2 signal changes in basal ganglia, thalamus, midbrain, pontine nuclei (gray matter involvement)
• Changes may be subtle early

Important: Negative antemortem tests do NOT exclude rabies. Tests may need to be repeated.

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11. WHO EXPOSURE CATEGORIES & POST-EXPOSURE PROPHYLAXIS (PEP)

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12. POST-EXPOSURE PROPHYLAXIS (PEP) - DETAILED

Step 1 - Wound Care (IMMEDIATE - Most Critical Step):

• Wash wound thoroughly with soap and water for at least 15 minutes
• Irrigate with water or saline
• Apply iodine-containing solution (povidone-iodine) or 70% alcohol
• Do NOT suture the wound immediately (or use minimal sutures)
• Do NOT occlude the wound
• Antitetanus prophylaxis and antibiotics as needed

Step 2 - Rabies Immunoglobulin (RIG) for Category III:

• Provides passive immunity (immediate protection)
• Two types:
  • HRIG (Human Rabies Immunoglobulin): 20 IU/kg body weight
  • ERIG (Equine Rabies Immunoglobulin): 40 IU/kg body weight (skin test first; cheaper but more allergic reactions)
• Infiltrate as much as anatomically possible around the wound(s); remaining volume given IM at a distant site from vaccine
• Must be given on Day 0 only - before or with first vaccine dose
• Do NOT give in the same syringe as vaccine; do NOT give at the same anatomical site as vaccine

Step 3 - Rabies Vaccine:

Standard PEP Schedule (Intramuscular - IM):

• Essen (5-dose) regimen - Days 0, 3, 7, 14, 28 (1 mL IM in deltoid for adults; anterolateral thigh in children)
• Zagreb (4-dose) regimen - Day 0 (2 doses in both deltoids simultaneously), Day 7, Day 21

Intradermal (ID) Regimen (WHO-approved, cost-effective):

• 2-site ID (Thai Red Cross regimen): 0.1 mL ID at 2 sites on Days 0, 3, 7, 28

Vaccines available (cell-culture based):

• HDCV (Human Diploid Cell Vaccine)
• PCECV (Purified Chick Embryo Cell Vaccine) - e.g., Rabipur/RabAvert
• PVRV (Purified Vero Rabies Vaccine) - e.g., Verorab
• PDEV (Purified Duck Embryo Vaccine)

Old nerve tissue vaccines (Semple, Fuenzalida/suckling mouse brain) are now obsolete due to high rates of neuroparalytic complications. WHO recommends all countries transition to cell-culture vaccines.

10-Day Observation Rule:

• If a healthy dog or cat bites and is available for observation:
  • Begin PEP immediately (Day 0)
  • If animal remains healthy after 10 days of observation, it is unlikely to have been infectious at the time of bite - vaccination can be discontinued
  • If the animal develops signs of rabies or dies, complete the full course

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13. PRE-EXPOSURE PROPHYLAXIS (PreP)

• Veterinarians and animal handlers
• Laboratory workers handling rabies virus
• Wildlife workers, spelunkers (cave explorers)
• Travelers to high-risk countries (long stay, remote areas)
• Children in endemic areas

Schedule:

• 3 doses of cell-culture vaccine: Days 0, 7, 21 or 28
• Given IM (deltoid) or ID
• Boosters: every 2 years for those at continuous risk (lab workers); or on the basis of serology (titer check every 2 years for intermittent risk)

Advantage:

• After pre-exposure, PEP requires only 2 booster doses (Days 0, 3) - NO RIG needed

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14. TREATMENT OF CLINICAL RABIES

• No proven effective treatment once clinical symptoms appear
• Aggressive supportive care (ICU):
  • Sedation (benzodiazepines, ketamine)
  • Analgesia
  • Anticonvulsants
  • Hydration, nutrition
  • Mechanical ventilation
• Milwaukee Protocol (experimental): ketamine, midazolam, ribavirin, amantadine - induced antiviral therapeutic coma; mixed results; only a few survivors reported
• Prognosis essentially fatal: survival extremely rare (6 documented cases worldwide as of 2025)

• Prior rabies vaccination
• Young age
• Immunocompetent
• New World bat variant rabies
• Early detection, early treatment initiation

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15. CONTROL & PREVENTION

1. Dog vaccination programs - mass canine vaccination is the most effective intervention globally; WHO target to eliminate dog-mediated human rabies by 2030
2. Pre-exposure immunization of high-risk humans
3. PEP for exposed individuals
4. Wildlife rabies control - oral bait vaccines in wildlife (Europe: red fox; North America: raccoons, coyotes)
5. Animal bite prevention education
6. Reporting all animal bites to public health authorities
7. Quarantine of biting animals for 10-day observation

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16. KEY POINTS TO REMEMBER

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