Rabies/Medical Therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Michael Maddaleni, B.S.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [3]

Overview

Two presentations must be considered in the treatment of rabies. Symptomatic patients with delayed presentation in the emergency department, associated with a low survival rate and treated with "Milwaukee protocol" (which is still being studied) and patients with a suspected exposure to rabies virus or early diagnosed asymptomatic rabies patients. Patients with suspected exposure to rabies or asymptomatic patients can benefit from thorough wound cleaning followed by a combined rabies vaccination and immune globulin administration, these patients have a good prognosis.

Medical Therapy

Two presentations must be considered in determining rabies treatment strategy:

• Symptomatic patients presenting to the emergency department
• Asymptomatic patients with a suspected exposure to rabies virus or early diagnosed asymptomatic rabies patients

Unfortunately the survival rate is very low in symptomatic patients. The treatment of choice for this group of patients is "Milwaukee protocol" which is still under further evaluation. Patients with suspected exposure to rabies or asymptomatic patients can benefit from a combined vaccine and immune globulin and have a good prognosis.

Rabies Treatment Algorithm

The treatment approach for rabies patients is summarized in the algorithm below:

Courtesy: CDC

Patient with Symptomatic Rabies

Milwaukee protocol

The Milwaukee protocol, also known as the Wisconsin protocol, is an experimental treatment approach for rabies infection in human beings. Milwaukee protocol involves induction of coma and administration of antiviral drugs. Ketamine as a part of Milwaukee protocol has been shown to have a direct effect against the rabies virus.

Clinical trials

Milwaukee protocol survival rate in symptomatic patients is around 14% far by now, compared to 0% survival rate among symptomatic patients. Out of 36 symptomatic rabies patients treated with the Milwaukee Protocol, 5 have survived. Milwaukee protocol regimen include suppression of brain activity by the administration of midazolam along with ketamine and combating the virus with amantadine and ribavirin until signs of immune system activity appear, has undergone revision (the second version omits the use of ribavirin). Two of the 25 patients treated under the first protocol survived. A further two out of 10 patients who were treated under the revised protocol, survived.

Some critics say as a certain antibody type appears in all survivors, the rabies disease survivors are not benefiting from the Milwaukee protocol, but their survival is due to a genetic immunity against rabies. This suggests that genetics or other immunological factors may affect survival. However surviving rabies infection started immediately after Milwaukee protocol introduction, as there were no documented survivors before them.

Asymptomatic Patient Suspicious of Rabies

Treatment management in these patients start with wound care, postexposure vaccination, and human immune globulin injection:

Wound Care

In the wound treatment procedure, cosmetic issues should be considered. Wound treatment procedure include immediate gentle wound irrigation with water or a dilute water povidone-iodine solution.

Rabies Post-exposure Vaccinations

In countries or areas at risk of rabies (based on WHO rabies distribution map), an animal bite or contact with a suspected rabid animal require post-exposure prophylaxis. WHO guidelines are the reference sources in disease management.

Post-exposure prophylaxis recommendations based on contact type

Category	Type of contact with a suspected or confirmed rabid domestic or wild (a) animal or animal unavailable for testing	Type of exposure	Recommended post-exposure prophylaxis
I	Touching or feeding animals Licks on intact skin	None	None, if reliable case history is available
II	Nibbling of uncovered skin Minor scratches or abrasions without bleeding	Minor	Administer vaccine immediately (b) Treatment can be withhold if animal remains healthy throughout an observation period of 10 days (c) or is proved to be negative for rabies by a reliable laboratory using appropriate diagnostic techniques.
III	Single or multiple transdermal bites or scratches, licks on broken skin Contamination of mucous membrane with saliva Exposures to bats (d)	Severe	Administer rabies immunoglobulin and vaccine immediately Stop treatment if animal remains healthy throughout an observation period of 10 days (c) or is proved to be negative for rabies by a reliable laboratory using appropriate diagnostic techniques

a) Exposure to rodents, rabbits and hares seldom, if ever, requires specific anti-rabies post-exposure prophylaxis.

b) If an apparently healthy dog or cat in or from a low-risk country or area is placed under observation, the situation may warrant delaying initiation of treatment.

c) This observation period applies only to dogs and cats. Except in the case of threatened or endangered species, other domestic and wild animals suspected to be rabid should be humanely killed and their tissues examined for the presence of rabies virus antigen using appropriate laboratory techniques.

d) Post-exposure prophylaxis should be considered for individuals who have been in close contact with bats, particularly following bites or scratches or exposure to mucous membranes. Even aerosol in the places with rabid bats can lead to disease.

Rabies Vaccines and Immunoglobulin Available in the United States

Type	Name	Route	Features	Indications
HDCV	Imovax® Rabies	IM	Contains the Pitman-Moore L503 or Flury strain of rabies virus grown on MRC-5 human diploid cell culture, concentrated by ultrafiltration and inactivated with ß-propiolactone	Preexposure or Postexposure
PCEC	RabAvert®	IM	Sterile lyophilized vaccine obtained by growing the fixed rabies virus strain Flury LEP-25 in primary cultures of chick fibroblasts. The virus is inactivated with ß-propiolactone, purified and concentrated by zonal centrifugation	Preexposure or Postexposure
HRIG	Imogam® Rabies-HT	Local infusion at wound site, with additional amount intramuscular at site distant from vaccine	The purification of immunoglobulins from human plasma	Postexposure
HRIG	HyperRab TM S/D	Local infusion at wound site, with additional amount intramuscular at site distant from vaccine		Postexposure

IM: Intramuscular, HDCV: Human Diploid Cell Vaccine, PCEC: Purified Chick Embryo Cell Vaccine, HRIG: Human Rabies Immune Globulin.

Rabies postexposure prophylaxis (PEP) schedule

Vaccination status	Intervention / Regimen
	Wound cleansing	HRIG	Vaccine
Not previously vaccinated	Immediate thorough cleansing of all wounds with soap and water Applying virucidal agent (e.g., povidone-iodine solution) to irrigate the wounds may be helpful	Administer 20 IU/kg body weight If anatomically feasible, the full dose should be infiltrated around and into the wound(s), and any remaining volume should be administered at an anatomical site (intramuscular [IM]) distant from vaccine administration	HDCV or PCECV 1.0 mL, IM, 1 each on days 0, 3, 7 and 14
Previously vaccinated		Not required	HDCV or PCECV 1.0 mL, IM, 1 each on days 0 and 3

HRIG= Human rabies immune globulin, PEP= Postexposure prophylaxis, HDCV=Human diploid cell vaccine, PCECV= Purified chick embryo cell vaccine, IM= Intramuscular

Considerations:

• Previously vaccinated persons are anyone with:
  • A history of pre-exposure vaccination with HDCV, PCECV, or rabies vaccine adsorbed (RVA)
  • Prior PEP with HDCV, PCECV or RVA
  • Previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination
• For persons with immunosuppression, rabies PEP should be administered using all 5 doses of vaccine on days 0, 3, 7, 14, and 28
• These regimens are applicable for persons in all age groups, including children
• The best location for IM vaccine injection is in deltoid muscle, gluteal area should be avoided
• HRIG should not be administered in the same syringe as vaccine
• As HRIG might partially suppress active production of rabies virus antibody, no more than the recommended dose should be administered

Adverse Reactions to Rabies Vaccine and Human Rabies Immune Globulin

Adverse reactions to rabies vaccine and immune globulin are not common. Newer vaccines in use today cause fewer adverse reactions than previously available vaccines. The most common adverse reaction reported with rabies vaccine/immune globulin injection include:

• Mild local reactions to the rabies vaccine, such as:
  • Local pain
  • Injection site erythema
  • Injection site swelling
  • Injection site itching at the injection site
• Rarely, general symptoms may develop following rabies vaccine, such as:
  • Headache
  • Nausea
  • Abdominal pain
  • Muscle aches
  • Dizziness
• Local pain and low-grade fever may follow injection of rabies immune globulin.

Human Rabies Immune Globulin

Human rabies immune globulin (HRIG) should be administered only once, at the beginning of anti-rabies prophylaxis, and is indicated just in previously unvaccinated persons. This will provide immediate antibodies until the body can respond to the vaccine by actively producing antibodies of its own.

If HRIG was not administered immediately when vaccination was begun, it can be administered up to seven days after the administration of the first dose of vaccine. Beyond the seventh day, HRIG is not recommended since an antibody response to the vaccine is presumed to have occurred.

Dosage:

• Preferred regimen: Because HRIG can partially suppress active production of antibody, no more than the recommended dose should be administered. The recommended dose of HRIG is 20 IU/kg body weight. This formula is applicable to all age groups, including children.

References

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