25. RABIES Flashcards
DEFINITION of RABIES
Rabies is a rapidly progressive, acute zoonotic infectious disease of the CNS in humans and animals that is cause by rabies virus.
It is one of the oldest and most feared human infection with the highest case fatality rate of any infectious disease.
ETIOLOGY
Although it was initially thought that a single virus was responsible for all rabies cases, rabies appears to be caused by different species of neurotropic viruses. In the Rhabdoviridae family, genus LYSSAVIRUS.
The bullet-shaped, Lyssavirus contains a ssRNA genome encoding 5 structural proteins. One of these genes encode for an outer glycoprotein which is a primary target for virus-neutralizing antibodies. In developing countries, rabid dogs account for >90% of cases transmitted to humans. Other animals that can serve as reservoir for the virus are bats, cats, racoons and foxes.
Rats and other rodents can be infected but cannot transmit the infection to humans
PATHOGENESIS
After the virus is inoculated primarily through 1) saliva 2) an animal bite or 3) scratch… the virus remains at the site of entry during incubation period which may last anywhere from 20 to 90 days. This is the usual interval of time between exposure and appearance of clinical disease. Interval may be shorter or longer.
In the Philippines, there have been cases of rabies wherein the incubation period was only 3 days while the longest incubation period recorded was 27 years.
Going back, in the muscles where it undergoes replication, the virus binds to NICOTINIC ACETYLCHOLINE RECEPTORS on post-synaptic membranes at Neuromuscular Junctions.
Rabies virus then spreads CENTRIPETALLY along peripheral nerves toward the CNS at a rate of up to 250 mm/day via RETROGRADE FAST AXONAL TRANSPORT along neuroanatomic connections such as the brain/spinal cord
After CNS infection becomes established, CENTRIFUGAL SPREAD then occurs along sensory and autonomic nerves, reaching the salivary glands, heart, adrenals and skin
Rabies will continue its replication in these areas especially in the ACINAL CELLS of SALIVARY GLANDS and is secreted in the saliva.
The basis for the behavioral changes including the aggressive behavior in animals and humans is not WELL UNDERSTOOD but it is proposed that NEURONAL DYSFUNCTION rather than neuronal death is responsible for the clinical disease in rabies
CLINICAL MANIFESTATIONS
The clinical manifestations of rabies begin with nonspecific prodromal manifestations including fever, malaise, headache, nausea and vomiting
Anxiety and agitation may also occur.
The earliest specific neurologic symptoms of rabies include paresthesias, pain or pruritus near the site of exposure.
The wound has usually healed by this point, and these symptoms probably reflect infection with associated inflammatory changes in local rosal root or cranial sensory ganglia.
After several weeks or months, patients with rabies will now exhibit acute neurologic features which may either be:
- Encephalitic/Furious Rabies (80%)
- Paralytic/Dumb Rabies (20%)
Encephalitic Rabies (80%)
The encephalitic form of rabies, the disease usually presents as atypical encephalitis with relative preservation of consciousness.
Other manifestations include: fever, confusion, hallucinatios, combativeness and seizures.
Autonomic dysfunction is common and may result in:
- Hypersalivation
- Goose flesh
- Cardiac arrhythmias
- Priapism
Episodes of hyperexcitability are typically followed by periods complete lucidity that becomes shorter as the disease progresses.
Rabies encephalitis is also distinguished by early brainstem involvement which results in classic features of:
- 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.
These symptoms are probably due to dysfunction of infected brainstem neurons that normally inhibit inspiratory neurons near the nucleus ambiguus, resulting in exaggerated defense reflexes that protect the respiratory tract,
The combination of hypersalivation and pharyngeal dysfunction is responsible for the classic appearance of “foaming at the mouth”
Brainstem dysfunction progresses rapidly, and coma followed within days by death is the rule unless the course is prolonged by supportive measures.
with such measures, late complications include:
- Cardiac/respiratory failure
- Disturbances in water balance (SIADH or DI)
- Noncardiogenic Pulmonary Edema
- GI Hemorrhage
Multiple Organ Failure is common in patients treated aggressively in critical care units.
Paralytic Rabies (20%)
In paralytic rabies, muscle weakness predominates and cardinal features of encephalitic rabies (hyperexcitability, hydrophobia, and aerophobia) are lacking
There is early and prominent flaccid muscle weakness, often beginning in the bitten extremity and spreading to produce quadriparesis and facial weakness.
Sphincter involvement is common
Sensory involvement is usually mild and is commonly misdiagnosed as GBS.
Patients with paralytic rabies generally survive a few days longer (2-10 days) than those with encephalitic rabies (2-7 days), but multiple organ failure nevertheless ensues.
CLINICAL STAGES of RABIES and time duration
- Incubation period (20 to 90 days)
- Prodromal stage (2 to 10 days)
- Acute neurologic disease (2 to 10 days) - encephalitic, paralytic
- Coma, death (0 to 14 days)
Diagnosis
Most routine laboratory results like CBC and blood chemistry in rabies yield normal or nonspecific results
Currently, there is no diagnostic tool available which is economically suitable in our country to confirm rabies and only supportive care is given once acute neurologic disease has ensued.
In an ideal setting, once rabies issuspected, rabies-specific laboratory tests should be performed to confirm the diagnosis.
Diagnostically useful specimens include Serum, CSF, Fresh Saliva, Skin Biopsy from the nape (cutaneous nerves from base of hair follicle) and brain Tissue of the biting animal and rarely of the host.
Different laboratory test which are used to diagnose rabies but are not available in the Philippines include:
- Rabies Virus Specific Antibodies - in a previously unimmunized patient, presence of Serum and CSF neutralizing antibodies to virus is diagnostic.
However, since Rabies infects immunologically privileged neuronal tissues, antibodies may not develop until late in the disease.
- RT-PCR Amplification
This is a highly sensitive and specific test to detect rabies virus RNA in fresh saliva samples, CSF and brain tissue - Direct Fluorescent Antibody Test - GOLD STANDARD **
Also a highly sensitive and specific test employing the use of rabies virus antibodies conjugated to fluorescent dyes
It is used to detect rabies antigen in skin biopsies and brain tissue.
The utility of these diagnostic tests in patients with obvious signs and symptoms of rabies is generally low considering the outcome of the disease.
These tests should only be used when the diagnosis of rabies is uncertain.
Differential Diagnoses
Occasionally, the diagnoses of rabies may be difficult especially when no exposure to an animal is recalled. (Ex. Bats in cave)
It may be confused with other causes of viral encephalitis such as:
HSV enceph
Japanese B enceph
Post-infection encephalomyelitis (influenza, measles, and mumps)
It may also mimic anti-NMDA receptor encephalitis which usually presents with behavioral changes, autonomic instability, hypoventilation and seizures.
Paralytic rabies may mimic GBS which in turn may also occur as a complication of rabies vaccination with neural tissue-derived product.
Management
There is no established treatment for rabies once acute neurologic symptoms have set in.
A palliative approach is typically pursued in patients who are unlikely to survive or who would not accept survival with severe neurologic sequelae.
This involves placing the patient in a quiet room.
Pharmacologic restrains are preferred using BENZODIAZEPINES over PHYSICAL RESTRAINTS.
IV MORPHINE may be given for analgesia, anicholinergics such as SCOPOLAMINE and GLYCOPYRROLATE for excessive salivation and antipyretics for fever.
On the other hand, in more advanced countries, an AGGRESSIVE APPROACH is sometimes used.
This involves following the MILWAUKEE PROTOCOL or WISCONSIN PROTOCOL which starts by putting the patient into chemically-induced coma using high-dose anesthetic agents as well as use ofmultiple intrathecal anti-viral drugs.
Using this protocol, tehre have been reported cases of survival, however with moderate to severe neurologic sequelae.
Prognosis
generally, rabies is an almost uniformly fatal disease and most patients die within several days of disease onset despite aggressive care.
Fortunately, there are available ways to prevent the disease after being exposed to animal bites.
PREVENTION
Post Exposure Prophylaxis
There are 2 types of prevention for rabies:
- Post-exposure prophylaxis - for patients who have been previously exposed to animal bites or scratch
- Pre-exposure prophylaxis - for individuals who are at constant risk of being exposed to rabies virus
POST-EXPOSURE PROPHYLAXIS
The first thing to do is to properly clean the wound regardless of the severity of the animal bite or scratch
The wound must be vigorously washed and flushed with soap and water for at least 10 minutes
Alcohol, povidone iodine or any other antiseptic may also be used but these are less effective than soap and water.
For frankly infected open wounds, ANTIBIOTICS may be started. CO-AMOXICLAV or CEFUROXIME will cover for Pasteurella multocida & s. Aureus
Tetanus Toxoid should be given and if the bite only happened within the past 24 hours, Tetanus Immunoglobulin can also be given. Animal bites are considered tetanus-prone wounds.
The category of the wound should be established followed by category-based intervention.
- Category I - touching or feeding suspected rabid animal; intact skin licked by suspected rabied animal
Management: non, wash hands and the area involved considered prEP
- Category II - nibbling of uncovered skin, minor scratches of abrasions without bleeding, wounds which have been induced to bleed
Licks on broken skin and mucous membrane - category III
Management - imemdiately start Active Immunization (0-3-7-28/30) intradermal
If animal remains alive after 10 to 14 days - discontinue after day 7
If animal becomes rabied, dies or is unavailable - continue until day 28/30
- Category III - transdermal bites (puncture wounds, lacerations, avulsions), licks on broken skin or mucous membrane, exposure to rabies patient through bites, unprotected handling of infected carcass, ingestion of raw infected meat, exposure to bats, stray animal bites, biting animal is sick or dead upon consult
All category II exposures on head and neck
Management: active immunization similar to category II exposures n head and neck
Management - Active immunization similar to category II + Passive immunization
ACTIVE IMMUNIZATION vs PASSIVE IMMUNIZATION
There are 2 types of Rabies Vaccine 1. Purified Vero cell Rabies VAccine (PVRV) and 2. Purified Chick Embryo Cell Vaccine (PCECV)
ACTIVE IMMUNIZATION
In our country, to minimize the cost of PEP, intradermal regimen was introduced. However, in an ideal setting, rabies vaccine should be given intramuscularly except in patients with hematologic conditions where IM injection is contraindicated.
Nevertheless, immunocompromised patients such as those with HIV, cancer and patients with chronic liver disease, those taking chloroquine and systemic steroids should be given standard IM regimen as the response to ID regimen is not optimum for these conditions.
INTRADERMAL REGIMEN - one dose of 0.1 mL PVRV/PCECV given on each deltoid should produce 3 mm wheal on the anterolateral thigh in infants on days 0,3,7,28/30 with a total of 4 doses or 4 visits
If animal remains alive after 10 to 14 days, no need for day 28/30
If animal becomes rabied, dies or unavailable (continue until day 28/30)
Intramuscular regimen - one dose of 0.5 mL PVRV or 1 mL PCECV given on one deltoid (anterolateral thigh in infants) on days 0,3,7,14,28/30 with a total of 5 doses, 5 visits.
PASSIVE IMMUNIZATION - passive immunization with RIg is given in combination with rabies vaccine to immediately provide neutralizing antibodies at the site of exposure before it becomes possible for the patient to produce his own Abs after vaccination
HRIg is preferred for patient with history of hypersensitivity to ERIg as well as symptomatic HIV patients.
2 types of RIg:
1. Human rabies immunoglobulin (HRIg) - 20 IU/kg, 150 IU/mL —> x0.133
T 1/2 - 24 days
- Equine Rabies Immunoglobulin (ERIg) - 40 IU/kg, 200 IU/mL —> x0.2
T 1/2 14 days
Total computed RIg should be infiltrated around and into the wound.
remaining RIg should be administered deep IM at a site distant from the site of vaccination
RIg should not exceed computed dose as it may reduce efficacy of the vaccine
If the computed dose is insufficient to infiltrate all bite wounds, it may be diluted with sterile saline 2-3 fold for through infiltration
RIg should ideally be given on the same day as the vaccine.
in case RIg is unavailable, it may still be given within 7 days after the first dose of the vaccine.
Beyond 7 days, RIg is not anymore indicated because an active antibody response to the rabies vaccine has already started.
RIg should never be given before the vaccine because it inhibits production of antibody by the vaccine.
Pre-exposure prophylaxis
PrEP is rabies vaccination administered before an exposure to potentially rabid animals
Individuals who should receive PrEP include:
- Health care workers directly involved in care of rabies patients
- Personnel in rabies diagnostic laboratories
- Pet owners and household members
- Animal handlers and field workers
- Veterinarians and veterinary students
- Spelunkers
- Children living in areas with high incidence of rabies
Both intradermal and intramuscular injections may be given with the same dosing as for PEP but is done on days 0,7,21/28
With regards to booster schedule, not all individuals who have complete PrEP should receive booster doses.
Only individuals with high risk exposures require boostershots done 1 year after primary immunization, then every 5 years
