A comprehensive review on Rabies: Clinical aspects and treatment

Surendar Sambath

Consultant and HOD of Emergency Medicine, Kauvery Hospital, Marathahalli

Introduction

Rabies is a dangerous zoonotic disease caused by Lyssavirus type 1. Rabies is an acute, progressive encephalomyelitis. The case-to-fatality rate is the highest of any infectious disease. 100% fatal yet nearly 100% preventable. The 40% of victims are children and they are usually bitten in the face/neck region

Reservoir of Infection

Domesticated animals: Dogs, cats, sheep, goats, cows, buffaloes, pigs, horses

Wild animals: Monkeys, mongoose, jackals, bears, foxes, and others

Rodents: Rats are not carriers of rabies

Modes of Transmission

Common Modes of Transmission

  • Animal bites
  • Licks, Scratches

Rare Modes of Transmission

  • Aerosols: Respiratory aerosol transmission can occur.
  • Human: Man-to-man transmission. Corneal & Organ transplants.

Incubation Period

3 weeks to 3 months (in > 85% cases).

The range is between 4 days to 4 years.

Bites on the head or face – up to 1 month.

Bites on the extremities –  upto 3 months.

Pathophysiology

Negri Bodies

Round or oval inclusions within the cytoplasm of nerve cells of animals infected with rabies. Vary in size from 0.25 to 27 µm.

Eosinophilic mass (Rabies virus + fine fibrillar matrix). Found most frequently in the pyramidal cells of Ammon’s horn, and the Purkinje cells of the cerebellum.

Clinical Manifestation in Humans

Furious Type (80%)Paralytic Type (20%)
Tingling/numbness at bite siteTingling / numbness at bite site
Nonspecific symptoms (Fever, malaise, headache, etc)Nonspecific symptoms (Fever, malaise, headache etc.)
Hydrophobia, AerophobiaAscending Paralysis
PhotophobiaComa
Death (cardio respiratory failure) Death (cardio respiratory failure)
Survival : 3 – 5 DaysSurvival : 7 – 21 Days

Wounds Categories

For the convenience in providing better treatment WHO has categorized animal bite wounds into 3 categories

CategoryType of contactRecommended PEP
I

  • Touching/feeding

  • Licks on intact skin

  • Contact of intact skin with secretions/excretions of rabid animal/human case


None, if reliable history is available
II

  • Nibbling of uncovered skin

  • Minor scratches or abrasions without bleeding



    • Wound management

    • Anti-rabies vaccine
III

  • Single or multiple transdermal bites

  • Scratches, licks on broken skin

  • Contamination of mucous membrane with saliva (i.e., licks)



  • Wound management

  • RIG

  • Anti-rabies vaccine

*> 90 percentage exposures are Category III, Any sight of Blood is a Category III exposure and carries the risk of rabies exposure

Management

Approach to Post Exposure Prophylaxis

Both are equal importance and should be done simultaneously as per the category of exposure

1. Management of Wound

2. Anti – Rabies Immunization

  • Active Immunization: Antirabies vaccine.
  • Passive Immunization: Rabies immunoglobulin (RIG) (in Category III exposures).

How long after the bite can the vaccine be started?

  • Immediately, before virus reaches nervous system
  • However, people who present for treatment even months or years after a possible rabies exposure should be evaluated and treated as if the event had occurred recently.
  • When in doubt start PEP

Wound toilet

  • Since the rabies virus enters the human body through a bite or scratch, remove as much saliva, and thereby the virus, from the wound by
  • Efficient wound toilet that should not involve additional trauma.
  • Since the rabies virus can persist and even multiply at the site of bite for a long time, wound toilet must be performed even if the patient reports late.
  • Do not touch the wound with your bare hand

Local Treatment of Wounds

  • Immediate and thorough washing of all wounds with soap & water for 10-15 minutes
  • Irrigate with a virucidal agent such as povidone iodine solution.
  • Tetanus prophylaxis
  • Antibiotics

Suturing of Wounds

  • Suturing should be avoided as every time the needle enters it could expose a nerve and help rabies virus entry.
  • In large wounds where suturing is unavoidable first inject the RIG around the wound.
  • Suturing should be delayed by several hours.
  • Minimum loose sutures should be applied.
  • The delay in suturing allows diffusion of antibodies in the tissues.

Classification of Rabies Vaccines

Nerve Tissue Vaccines (NTVs)

  • g. Semple vaccine

New Generation Vaccines

  • Purified Duck Embryo Vaccine (PDEV)
  • Purified Chick Embryo Vaccine (PCEV)
  • Purified Vero Cell Vaccine (PVRV)
  • Liquid Human Diploid Cell Vaccine (HDCV)

Modified Essen Vaccination Schedule

It includes 4 IM doses;

  • First, Dose – day 0
  • Second Dose – day 3
  • Third, Dose – day 7
  • Fourth Dose – Between day 14 and 28

Site of Injection: Deltoid Muscle in arm and anterolateral thigh (infants & children).

Never inject in Gluteus Muscle as there is high fat deposition which could delay absorption of vaccine and hence slow antibody production

Intra-dermal (ID) Regimen

  • Administration of a fraction of IM dose of approved vaccine on one or more than one site in the layers of the dermis
  • Less expensive
  • Useful in rural areas where the patient flow is high
  • Use vaccine within 8 hrs of reconstitution
  • Vaccine leaflet should have approval for IM/ID

Updated Thai Red Cross Schedule (2-2-2-0-2)

  • 1ml of vaccine per ID site and on 2 sites per visit
  • (one on each deltoid area, an inch above the insertion of deltoid muscle) on days 0, 3, 7 & 28.
  • Alternate areas are suprascapular & anterolateral thigh
  • Visible & palpable bleb on skin
  • If given SC/IM by mistake, another dose
  • should be given ID

Switch over from IM to ID route of administration or vice versa during PEP was not recommended as there is no sufficient scientific evidence/study on vaccine immunogenicity following changes in the route of vaccine administration during PEP.

 

Points to remember

  • Day 0 – Day 1st vaccine dose is given, not the day of bite.
  • All modern anti rabies vaccines are equally effective and safe.
  • Interchange of vaccines acceptable in special circumstances but not to be done routinely.
  • Reconstituted vaccine to be used immediately.
  • Vaccine dosage is same for all age groups.

Contraindications and Precautions

  • No adverse effect on pregnant woman, course of pregnancy, fetus, or lactating mother.
  • People taking chloroquine may have a decrease in response to ID, hence IM.
  • Observe all patients for at least 15–20 min following vaccination.
  • Previous reaction to any component of vaccine is a contraindication to the use of the same vaccine for PEP

Passive Immunisation

Rabies Immunoglobulins (RIG)

  • Equine antirabies immunoglobulin (ERIG)
  • Human antirabies immunoglobulin (HRIG)

Monoclonal Antibodies

  • Single Monoclonal Antibody (3.33 IU/kg)
  • Cocktail of two Monoclonal Antibodies (40 IU/kg)

Role of immunoglobulins

  • High viral load at the site of the bite
  • Vaccine provides active immunization
  • After the vaccine, the body takes upto 10–14 days to make antibodies.
  • Hence vaccine offers protection only after 10–14 days
  • Incubation period of rabies can be as short as 3 days.
  • Hence, vaccine alone is not protective in Class 3 bites.
  • RIG helps bridge the gap between vaccination and the time it takes for the body to begin producing its own antibodies.

RIG Indications

  • All Category III exposures including those in pregnant women and lactating mothers.
  • Bites by all wild animals viz. by mongoose, jackal, fox and others.
  • Even Category II exposures in immunocompromised or immunosuppressed individuals eg. HIV.

Dosage

Equine antirabies immunoglubulin (ERIG) – 40IU/Kg

Human antirabies immunoglubulin (HRIG) – 20IU/Kg

Site of injection

RIG should always be injected around the wound.

In case of a big wound the RIG can be diluted in NS and inserted around the wound

IM injection is not advocated and not effective

The RIG should be brought to room temperature (25ºC to 30ºC) before administration to the patient.

Local infiltration of RIG

RIG binds with the rabies virus, resulting in neutralization & loss of infectivity of the virus. Hence, it is logical to infiltrate RIG locally at the site of exposure. Should be infiltrated in the depth and around the wound(s) to neutralize the locally present virus. Avoid multiple injections into the wound

Timing of RIG

Administer only once, preferably within 24 hr after the exposure i.e. on day 0 along with the first dose of anti-rabies vaccine. If RIG was not administered when ARV was begun, it can be administered up to the 7th day after the administration of the first dose of ARV.

Beyond the seventh day, RIG is not indicated since an antibody response to ARV would have occurred and administration of RIG at this stage can suppress the immune response of the patient to the ARV received.

Why Passive Immunization is important

ERIG

  • ERIG is of heterologous origin produced by hyper immunisation of equines.
  • Currently manufactured ERIGs are highly purified Fab 2’ fragments and occurrence of adverse events has significantly decreased
  • Small risk of anaphylactic reaction (1/150,000).
  • Do not do a skin test as it does not predict reactions & ERIG should be given irrespective
  • Be ready to treat anaphylaxis if it occurs.

HRIG

Sterile solution of antirabies immunoglobulin derived from human serum.

  • Element of purity
  • Minimal or no foreign protein
  • No chance of immediate hypersensitivity
  • Negligible side effects
  • Can be administered safely in high risk patients like pregnant women, children, elderly and immunocompromised states.

Common fallacies and facts on PEP usage

FallaciesFacts

  • Only multiple bites warrant passive immunization

  • Only big bites or deep wounds require passive immunization

  • Only bites on the face, chest, or upper extremities warrant passive immunization

  • Complete PEP for category 3 exposure comprises of anti-rabies vaccine only


All bites (big/small, superficial/deep, single/multiple) with a sight of blood anywhere on the human body from a suspected rabid animal requires a complete PEP.

*Overcoming the challenges – Need for a Novel Prophylactic Option ‘Cocktail of 2 mAbs’.

Monoclonal antibodies

Recommended by WHO, Cocktail containing at least 2 antibodies against RABV with non overlapping epitopes. A single monoclonal antibody product (mAb) has been found to be effective. Few products have been licensed by DCGI in India and it was a Replacement for RIG.

Advantages of Monoclonal antibodies

  • mAbs can be produced with standardized quality in large quantities. Do not use animals in the production process.
  • High effectiveness
  • Reduced risk of adverse events

Post-exposure prophylaxis of immune-compromised patients

  • Patients on chemotherapy, steroid therapy, cancer patients, etc
  • Thorough wound toilet
  • Immunoglobulin and vaccination
  • Anti-rabies antibody estimation 14 days after completion of vaccination to assess need of additional doses of vaccine.

Protective level of anti-rabies antibody

  • Anti-rabies neutralizing antibody titre of 0.5 IU/ml or more in serum is considered as protective.
  • This level is achieved in most healthy individuals by day 14 of a postexposure regimen

WHO recommendation for treatment for re-exposure

  • Re-exposure after a full course of documented pre / post –exposure vaccination
  • 2 active immunization schedules
  • Proper wound toilet
  • No RIG is required even if re-bite is of category-III
  • No need of vaccines in case a full dose of PEP has been taken in the last 3 months.

Short rabies PEP of previously vaccinated patients

Schedule 1

  • One dose to be injected IM/ID on days 0 and 3

Schedule 2

  • 4 site ID
  • 4 injections of 0.1 ml distributed equally over left & right deltoids, thigh or suprascapular areas in a single visit

How long does immunity last after PEP

The development of immunological memory after vaccination is critical for the establishment of long lasting immunity against rabies in humans.

Individuals who had received their primary series 5–21 years previously showed good anamnestic responses after booster vaccination.

Full PEP should be given to the following patients after re-exposure

All incomplete/partial/doubtful vaccinations are treated as fresh cases. Where immunological memory is no longer assured as a result of HIV/AIDS or other immunosuppressive causes

Causes of Treatment Failure

  • Insufficient wound treatment
  • Non administration of RIG
  • Incomplete infiltration of all wounds with RIG
  • RIG given intramuscularly and not around wound
  • Delay in starting and incomplete treatment
  • Intra-gluteal injection of cell culture vaccine.

Signs of Rabies in Dogs/Cats during 10 Day Observation Period

  • Any change in behaviour – undue aggression/depression.
  • Running aimlessly and attacking others without any provocation.
  • Becomes too drowsy and withdraws itself to a corner.
  • Excessive Salivation.
  • Change in voice.
  • Refusal to feed or eating unusual objects like stones, papers, wood, metal pieces etc.
  • Death of animal.
  • Special Conditions

Wild Animal Bites

All wild animal bites are category III -regardless of their severity.

Bird Hits

It is extremely unlikely for birds living free in nature to be infected with Rabies Virus

 

Pre-Exposure Prophylaxis (PrEP)

  • PrEP is vaccination in preparation for potential risk of exposure to RABV
  • PrEP is recommended for individuals at higher risks due to occupation or for sub-populations in remote rabies-endemic settings.
  • PrEP makes administration of RIG unnecessary after a bite wound
  • Previously immunized individuals benefit from abridged PEP in case of exposure to RABV

PrEP Dosage

  • One dose of vaccine IM or 0.1 ml ID on days 0, 7 , 21/28.
  • Neutralizing antibody titres checked every 6 months during the initial 2 years after the primary vaccination.
  • If it is less than 0.5 IU/ml a booster dose of vaccine should be given.
  • Sero-monitoring every 2 years.
  • Because vaccine-induced immunological memory persists in most cases for years, a booster would be recommended only if rabies virus neutralizing antibody titers have dropped to less than 0.5IU/ml.
  • Such individuals on getting exposed to rabies virus after successful pre-exposure immunization require only 2 booster injections of vaccine given on days 0 and 3 and no RIG

Summary

  • Rabies post exposure treatment should be started as soon as possible.
  • Wounds should be washed immediately
  • Passive immunization for all category 3 bites.
  • Do not delay treatment while observing the dog.
  • Pregnancy & infancy are not contraindications.
  • Patients who come months after being bitten should also be given 4 doses of the vaccine.

Conclusion

Rabies is 100% fatal, and 100% preventable disease. India accounts for 1/3 of the world’s rabies deaths. For treatment, WHO recommends RIG/MABs + Vaccine for category III bites. Cocktail of 2 MABs, convenient to use and well tolerated.

It is very important for us to understand and implement the above to achieve the goal of zero deaths due to rabies by 2030.

Dr. Surendar Sambath
HOD – Emergency

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