RABIES

I. Definition and Etiology

II. Pathophysiology, Classifications
III. Clinical Manifestations (History and PE)
IV. Differentials
V. Diagnostics
VI. Treatment
VII. Prevention

References:
1. Harrison’s Principles of Internal Medicine 21st edition
2. 2018 DOH guidelines on the management of rabies exposure

DEFINITION AND ETIOLOGY

Rabies is a rapidly progressive, acute infectious disease of the CNS that is caused by infection with
rabies virus. Rabies has encephalitic and paralytic forms that progress to death.

The infection is transmitted from animal vectors via a bite exposure, hence rabies is considered a
zoonotic infection. Transmission from non-bite exposures is uncommon, but examples include aerosols
generated in the laboratory or in caves, corneal transplantation and also solid-organ transplantation from
donors with undiagnosed rabies.

Worldwide, most human rabies is transmitted from dogs in countries with endemic canine rabies and
dog-to-dog transmission.

PATHOPHYSIOLOGY

The virus that causes rabies is a member of the family Rhabdoviridae under the family Lyssavirus. The
virus can infect a broad range of mammals.

1. When a human is bitten by a rabid dog, the virus is inoculated into the muscle, where it
replicates
a. Coincides with the incubation period (20-90 days, but in rare cases is either as short as
a few days or > 1 year), during which the virus is present at or close to the site of
inoculation
b. Post-exposure prophylaxis is only effective during this period
2. Virus then binds to nicotinic ACh receptors at the postsynaptic membrane of the
neuromuscular junction
3. Virus travels via retrograde fast axonal transport within axons in peripheral nerves
a. Rate of around 250 mm/day
4. Virus replicates in motor neurons of the spinal cord and local dorsal root ganglia and
rapidly ascends to the brain
a. Infection in the dorsal root ganglia results in pain, paresthesia, and pruritus at the
exposure site
b. Autonomic dysfunction → hypersalivation, gooseflesh, arrhythmia, priapism
 c. Once the virus enters the CNS, it rapidly disseminates to other regions of the CNS via
fast axonal transport
d. Brainstem involvement → dysfunction of neurons that normally inhibit inspiratory
neurons near the nucleus ambiguus → exaggerated reflexes that protect the respiratory
tract
5. Infection of the brain causes neuronal dysfunction (since there is lack of prominent
degenerative neuronal changes)
a. Infection of astrocytes is unusual
b. Causes mild inflammatory changes disproportionate to the clinical severity and fatal
outcome
c. The most characteristic pathologic finding is the Negri body (eosinophilic cytoplasmic
inclusions in brain neurons composed of rabies virus proteins and viral RNA)
i. Commonly in Purkinje cells of the cerebellum and pyramidal cells of the
hippocampus
d. Infection of serotonergic neurons results in behavioral changes
6. Virus spreads centrifugally along sensory and autonomic nerves to salivary glands, skin, cornea,
and other organs
a. May also spread to the heart, adrenal glands
b. Virus replicates in acinar cells of the salivary glands and is secreted in the saliva of rabid
animals that serve as vectors of the disease
c. No hematogenous spread

CLINICAL MANIFESTATIONS

Incubation period No symptoms

Prodromal features ● Paresthesia, pain, pruritus at the healed wound

● Fever, malaise, anorexia, headache, nausea, and vomiting
● Anxiety, agitation

Acute neurologic disease

Encephalitic/furious ● Fever, confusion, hallucinations, combativeness, seizures

rabies (80%) ● Episodes of hyperexcitability followed by periods of complete
lucidity that become shorter as the disease progresses
● Autonomic dysfunction (hypersalivation, gooseflesh, cardiac
arrhythmia, priapism)
● Early brainstem involvement
○ Hydrophobia (involuntary, painful contraction of the
diaphragm and accessory respiratory, laryngeal, and
pharyngeal muscles in response to swallowing liquids)
○ Aerophobia (same features caused by stimulation from a
draft of air)
● Foaming at the mouth because of hypersalivation + pharyngeal
dysfunction
● Rapid progression (coma followed within days by death)

Paralytic/dumb rabies ● Flaccid muscle weakness predominates

(20%) ○ Begins in the bitten extremity and spreads to produce
quadriparesis and facial weakness
○ Sphincter incontinence (may be misdiagnosed as GBS)
 ● No hyperexcitability, hydrophobia, aerophobia
● Survive a few days longer than those with encephalitic rabies

HISTORY
● Symptoms of rabies (prodromal features, symptoms of neurologic disease)
○ When did symptoms start to occur in relation to the exposure?
○ Presence of lucid intervals? (differentiates rabies from other viral encephalitides)
● Exposure history
○ When did the bite occur? Has the wound healed? Did it bleed spontaneously?
○ Animal involved? Rabid-looking? Wild or domestic? Is the animal still alive?
■ Rabid dog will die within 10 days from the time of biting
○ Was the bite provoked or unprovoked?
○ Any first aid measures performed?
○ Exposure to patients with suspect or proven rabies?
● Occupational history (veterinarian?)
● Vaccination history (pre-exposure prophylaxis? Any other rabies immunization in the past?)
○ Also ask about tetanus immunization status

PHYSICAL EXAMINATION
● Examine the wound (location, spontaneous bleeding, signs of infection)
● Level of consciousness, combativeness/agitation
● Vital signs
● Neurological examination
○ Minimal sensory deficits

DIFFERENTIAL DIAGNOSIS

Other viral encephalitides ● Impaired consciousness without lucid intervals

(HSV encephalitis) ● No history of animal bite exposure
● Late brainstem involvement
● No neurologic symptoms at the site of the bite (pain,
paresthesia, pruritus)

Autoimmune (anti-NMDA) ● Young female patients with behavioral changes, autonomic

encephalitis instability, hypoventilation, and seizures

Guillain-Barré syndrome ● May mimic paralytic rabies

● Fever, bladder dysfunction, normal sensory examination,
and CSF pleocytosis favor a diagnosis of rabies

DIAGNOSTICS

Laboratory exams are only useful at the onset of clinical manifestations

Direct fluorescent ● Gold standard

antibody test (DFAT) ● Fluorescent-labeled antibody is incubated with rabies-suspect brain
tissue (dogs) or skin biopsy → bind to rabies antigen → (+)
 apple-green fluorescence

Skin biopsy ● Specimen from the nape (detect antigen in the cutaneous nerves at
the base of the hair follicles)
● May do DFAT

Brain biopsy ● Specimen from the dead animal’s brain

● Check for Negri bodies
● May do DFAT

RT-PCR ● Detection of virus RNA from fresh saliva samples, skin biopsy, CSF,
brain tissue
● Not usually done

CSF examination ● If suspecting other treatable diagnosis (e.g., HSV encephalitis)

● CSF findings in rabies: mild mononuclear pleocytosis with a mildly
elevated protein level

Negative antemortem tests never exclude a diagnosis

TREATMENT

There is no established treatment for rabies (uniformly fatal but is nearly always preventable after
recognized exposures with appropriate post-exposure therapy during the early incubation period)

GOALS
1. Decrease the viral burden
2. Neutralize/decrease in the virus in the body
3. Supportive care/palliative care

Isolate the patient and limit the number of healthcare workers who will come in contact with the patient
● Quiet, draft-free isolation room
● IV fluids
● Avoid invasive procedures
● Provide emotional and physical support
● Discuss among relatives possible PEP among contacts
● Give honest prognosis (90% fatality)
● Arrange for transfer to a hospital or institution that handles patients with rabies (RITM or San
Lazaro)

Local wound treatment

● Immediately and vigorously wash wound with soap and water for 10 minutes
● Debride devitalized tissues
● Apply alcohol, povidone iodine, or any antiseptic
● Do not apply anything that can contaminate the wound (tandok, bato, garlic, ointment, creams)
● Avoid suturing the wounds (may inoculate virus deeper into the wounds)

Post-exposure prophylaxis
● Effective only during the incubation period (20-90 days) when the virus is still in the muscle
● Categorize the wound (Category I-III)
 CATEGORY MANAGEMENT

CATEGORY I

a. Feeding/touching an animal 1. Wash exposed skin immediately with soap

b. Licking of intact skin (with reliable history and water
and thorough PE) 2. No vaccine or RIG needed
c. Exposure to patient with signs and 3. Pre-exposure prophylaxis may be
symptoms of rabies by sharing of eating considered for high-risk persons
or drinking utensils
d. Casual contact (talking to, visiting, and
feeding suspected rabies cases) and
routine delivery of healthcare to patient
with signs and symptoms of rabies

CATEGORY II
1. Wash wound with soap and water
a. Nibbling of uncovered skin with or without 2. Start vaccine immediately
bruising/hematoma 3. Complete vaccination regimen until day 7
b. Minor superficial scratches/abrasions regardless of the status of the biting
without bleeding, including those induced animal
to bleed 4. RIG is not indicated

CATEGORY III

a. Transdermal bites (puncture wounds,

lacerations, avulsions) or
scratches/abrasions with spontaneous 1. Wash wound with soap and water
bleeding 2. Start the vaccine and RIG immediately
b. Licks on broken skin or mucous 3. Complete vaccination regimen until day 7
membranes regardless of the status of the biting
c. Exposure to a rabies patient through animal
bites, contamination of mucous
membranes (eyes, oral/nasal mucosa,
genital/anal mucous membrane) or open
skin lesions with body fluids through
splattering or mouth-to-mouth
resuscitation
d. Unprotected handling of infected
carcasses
e. Ingestion of raw infected meat
f. Exposure to bats
g. All Category II exposures on head and
neck area

Rabies vaccine
● Dosing: day 0, 3, 7, 28
○ First dose is given on the day of the exposure
○ Must be the same vaccine type for all doses
● Vaccine may be given IM or ID but IM is more reliable in terms of absorption
○ ID is cheaper due to lower volume required
○ For immunocompromised and pregnant patients, give IM at 1 site only (unreliable
absorption of ID dose)
 ○ Pregnancy and lactation are not contraindications for vaccination
● Intradermal regimen (one dose = 0.1 mL for both PVRV and PCECV)
○ One dose shall be given on each deltoid on days 0, 3, 7, 28
○ Vaccine should never be given around the gluteal area because of unpredictable
absorption

Purified Vero Cell Rabies Vaccine (PVRV) 0.5 Purified Chick Embryo Cell Vaccine (PCECV) 1
mL/vial mL/vial

ID: 0.1 mL ID: 0.1 mL

IM: 0.5 mL IM: 1.0 mL

● If patient was previously immunized:

○ Give booster doses: rabies vaccine on days 0 and 3
○ No RIG

Passive immunization with rabies immunoglobulin (RIG)

● Provide immediate availability of neutralizing antibodies at the site of exposure before it is
physiologically possible for the patient to begin producing his or her own antibodies after
vaccination
● Should not be given > 7 days post-exposure (patient is already producing antibodies → will
dampen immune response by antibody feedback)
● Given at the same time as the first dose of rabies vaccine (day 0) but at a separate site from
the rabies vaccine (will neutralize each other)
● The total RIG shall be infiltrated around and into the wound as much as anatomically feasible,
even if the lesion has healed
○ If with leftover RIG → may be reserved for the next patient who needs RIG
■ May also give the rest IM (adults: deltoid; children: anterolateral aspect of the
thigh)
○ If wound is big → dilute the RIG with sterile NSS to cover the entire area
○ If the exposure involves a mucus membrane → entire dose administered IM
● Observe the patient for at least one hour after injection of ERIG for immediate allergic reactions
○ If with anaphylaxis:
■ Give 0.1% epinephrine (1:1000) intramuscularly (0.5 mL for adults; 0.01 mL/kg in
children, maximum of 0.5 mL)
■ Repeat epinephrine dose every 10-20 minutes for 3 doses
■ Give steroids after epinephrine

Equine-derived rabies immunoglobulin (ERIG) Human-derived rabies immunoglobulin (HRIG)

● 40 IU/kg (200 IU/mL vial) ● 20 IU/kg (150 IU/mL vial)

● First-line because cheaper ● For special populations (pregnant,
● Do skin test before administration newborn, immunocompromised)

● RIG shall not exceed the computed dose as it may reduce the efficacy of the vaccine

Tetanus prophylaxis (animal bites are considered tetanus prone wounds)

● Fully vaccinated (3 or more doses), dirty/animal bite wound
 ○ If last dose was given within the last 10 years, no need to give anything
○ If it has been more than 10 years, give booster dose of tetanus toxoid
● Unvaccinated/incomplete vaccination (unknown or < 3 doses), dirty/animal bite wound
○ Tetanus toxoid (0, 1, 6 months) + TIG (250 IU single dose)
Antibiotic treatment
● The most common organism isolated from dog and cat bites is Pasteurella multocida
● Antimicrobials are recommended for:
○ All frankly infected wounds
○ All category III cat bites
○ All other category III bites that are either deep, penetrating, multiple, or extensive or
located on the hand/face/genital area
● Recommended antimicrobial regimens:
○ Co-Amoxiclav (adults: 500 mg TID; children: 30-45 mkday in 3 divided doses)
○ Cloxacillin (adults: 500 mg QID; children: 10-150-100 mkday in 4 divided doses)
○ Cefuroxime axetil (adults: 500 mg BID; children: 10-15 mkday in 2 divided doses)
○ For penicillin allergic patients (adults: doxycycline; children: erythromycin)
○ For instances where there are no obvious signs of infection, amoxicillin as prophylaxis
may suffice

PREVENTION

Pre-exposure prophylaxis
● For people with occupational or recreational risks of rabies exposure (veterinarians, people who
handle animals)
● Three doses of vaccine on days 0, 7, and 21 or 28

If the pet/animal is vaccinated against rabies, there is still a need for post-exposure prophylaxis