APCRI is an organization of like minded persons coming together to fight the menace of Rabies. It is probably the most feared of all human diseases. Many members of this association are physicians working in Anti-rabies clinics in the Govt sector or the Private sector . In most places of employment, no initiative is taken by the administration for updating the knowledge base of the physicians working there. The system is very happy if the attending patients are disposed off with the free or whatever doses of the vaccine that are available there with no untoward incident taking place. The doctors who have kept themselves updated have done so with their individual effort. In most cases the system has not helped them in any manner, but has put numerous obstacles in their path to acquire knowledge. Doctors acquire knowledge to equip themselves for providing better service to their patients. Patients come to the doctors for getting the best possible treatment for themselves. These are facts of life.

WHO Expert Consultation in Rabies meeting took place in Geneva, from 5th to 8th October 2004. In that meeting many aspects of Rabies the disease, its incidence, Classification of Lyssaviruses, Advances in diagnosis and the knowledge base in the Pathogenesis of Rabies, Management of Rabies patients before and after death, Rabies vaccines and immunoglobulins, Prevention of rabies in humans, National programmes for the control of rabies in dogs, Control of rabies in wild animals and “The Guide for post-exposure prophylaxis”, and many others were discussed and resolutions adopted and recorded. The report has been published in the web. In professional circles it is known as TRS 931.

In India, we have our own “National Guidelines for Management of Animal Bites” formulated in 2001, by a group of experts meeting in New Delhi at the National Institute of Communicable Diseases (NICD). The expert group consisted of eminent Clinical Practitioners managing anti-rabies clinics, Laboratory Medicine practitioners, Neuro-virologists, Neuro-physicians and vaccine manufacturers from both the Govt and Private sectors. The guidelines emerged from the consensus deliberations of the expert group. It was published in “C D Alert”, Volume 6 : No 3, March 2002. The News Letter CD Alert is the monthly news letter of the NICD, New Delhi. The issue containing the guidelines came with a Foreword by the Honurable Minister of Health and Family Welfare of the Govt of India.

In our effort to help the physicians in facing the “Challenges in the Management of Animal Bites”, we are enclosing in this issue of the “APCRI Journal” selected portions of the WHO TRS 931 and the National Guidelines for Management of Animal Bites. We will be very happy if these documents help the doctors in managing critical situations. In future also we will try our very best to publish most recent information on rabies.

WHO Technical Report Series 931
Prevention of rabies in humans

Vaccines used for the prevention of rabies in humans, including both pre- and post-exposure prophylaxis, should always meet WHO recommendations for production and control. Treatment for the prevention of rabies in humans exposed to rabies should begin as soon as possible after the exposure occurs. Treatment consists of thorough wound cleansing for a minimum of 15 minutes using water, soap and a virucidal antiseptic (e.g. povidone iodine or ethanol) followed by the administration of rabies passive immunization and cell-culture or purified embryonated egg rabies vaccine of proven efficacy. The initial treatment of severely exposed (category III) subjects must include injection of rabies immunoglobulin according to WHO recommendations . The Consultation strongly advocates the use of cell-culture or purified embryonated egg rabies vaccines that comply with WHO criteria for potency, immunogenicity, innocuity, and safety that have been satisfactorily assessed in well-designed clinical trials.

Pre-exposure vaccination

National authorities should provide guidance as to who should receive pre-exposure vaccination. Generally pre-exposure vaccination should be offered to people at high risk of exposure such as those working in rabies diagnostic or research laboratories, veterinarians, animal handlers (including bat handlers), animal rehabilitators and wildlife officers, as well as other people (especially children) living in or travelling to high-risk areas. Children under 15 years of age are the most frequently exposed age group, representing approximately 50% of human exposures in canine rabies-infected areas. Vaccines produced in cell culture or from embryonated eggs should be used for pre-exposure vaccination of humans. Pre-exposure vaccination is administered as one full dose of vaccine intramuscularly or 0.1 ml intradermally on days 0, 7 and either day 21 or 28. A few days’ variation is acceptable. Vaccine is administered into the upper arm (deltoid region) of adults and into the anterolateral thigh region of young children. Vaccine should never be administered into the gluteal region as absorption is unpredictable. Rabies vaccines having a potency of at least 2.5 IU per single intramuscular dose (NIH test) will induce long-lasting memory cells causing an accelerated immune response when a booster dose of vaccine is administered. People currently receiving malaria prophylaxis or who are unable to complete the entire three-dose pre-exposure series prior to initiation of malarial prophylaxis should receive pre-exposure vaccination by the intramuscular route. If the immune status of a patient is questionable at the time of vaccination, his or her immune response to the vaccine should be assessed after the three-dose pre-exposure series has been administered. Periodic booster injections are recommended for people who are at continual risk of rabies exposure. The following guidelines are recommended for determining when boosters should be administered.

All people who work with live rabies virus in a diagnostic or research laboratory or in vaccine production should have periodic antibody determinations to avoid unnecessary boosters.

People at continuous risk, e.g. rabies researchers, diagnostic laboratory workers (where virus is present continuously, often in high concentrations, and where specific exposures are likely to go unrecognized) should have serological testing every 6 months. Judging the relative risk of exposure and the monitoring of vaccination status is the responsibility of the laboratory supervisor. A booster is recommended if the titre falls below 0.5 IU/ml.

Responsible authorities should ensure that all people at risk are vaccinated and that serological status is monitored. A rabies pre-exposure certificate should be completed and given to the vaccinee indicating the type of vaccine and vaccine regimen used, lot number of vaccine, and any adverse reactions that occurred during vaccination.

Post-exposure prophylaxis
General considerations

All people exposed to rabies should promptly and thoroughly cleanse their wound(s) and apply appropriate antiseptics. Professional assistance is advised. This should be followed, if careful medical assessment requires it, by a complete vaccine series using a potent and effective vaccine that meets WHO criteria and passive immunization in category III exposure. A complete guide to post-exposure prophylaxis can be found in Table No:1. Strict adherence to the WHO recommended guidelines for optimal post-exposure rabies prophylaxis virtually guarantees protection from the disease. Rabies vaccines for human use that meet WHO requirements for production and control are safe and effective and are free from the neuroparalytic adverse reactions associated with nerve tissue-derived products. Pregnancy, infancy, old age and concurrent illness are not contraindications for rabies post-exposure prophylaxis in the event of an exposure. Prolonged incubation periods have been associated with human rabies; therefore people who present for treatment even months after a possible rabies exposure should be evaluated and treated as if the event had occurred recently. Factors that should be considered in deciding whether or not to initiate post - exposure prophylaxis include :

• nature of the contact or injury;

• presence of rabies in the area where the contact occurred or where the animal responsible originated;

• availability of the animal for laboratory examination or observation;

• species of the animal;

• clinical status of the animal responsible;

• vaccination history of the animal, and type and timing of vaccine used.

The decision to administer post-exposure prophylaxis after an exposure to an apparently healthy animal should be based on a careful risk assessment by a qualified medical professional. The risk assessment should consider the criteria outlined above. A history of rabies vaccination in an animal is not always a guarantee that the biting animal is not rabid. Animal vaccine failures may occur because of improper administration or poor quality of the vaccine, poor health status of the animal, and the fact that one vaccine dose does not always provide long-lasting protection against infection in dogs. Whether a dog bite was provoked rather than unprovoked should not be considered a guarantee that the animal is not rabid as it can be difficult to understand what an attacking dog considers provocation for an attack. If the animal involved in the exposure is a potential rabies vector in a rabies-endemic region, initiation of post-exposure prophylaxis should never await the results of laboratory examination, nor should the responsible animal be observed for signs of rabies prior to starting post-exposure prophylaxis. Wound treatment and administration of rabies biologicals, including a passive immunization product, when required, and vaccine, should be started as soon as possible after exposure. Immediate humane killing of the animal and examination of the brain at a reliable laboratory should be performed whenever possible. If the species involved is unlikely to be infected with rabies, treatment may be deferred pending the outcome of laboratory testing, providing that results can be obtained within 48 hours.

If the attacking animal is a pet dog or cat that is available, it should be kept under observation for 10 days, preferably under the supervision of a veterinarian. Prophylaxis can be discontinued if the dog or cat remains healthy for at least 10 days after the exposure occurred. The natural history of rabies in mammals other than dogs or cats is not fully understood and therefore the 10-day observation period may not be applicable. Humans exposed to other species of mammals suspected to be rabid, including bats and other wild animals involved in the transmission of rabies should therefore receive post-exposure prophylaxis unless the animal can be captured, humanely killed and immediately examined at a reliable laboratory.

Certificate of post-exposure prophylaxis

A certificate of post-exposure prophylaxis should be filled in and given to each vaccinee.

Complications of post-exposure prophylaxis Rabies immunoglobulins

Early local injection-site reactions consisting of erythema and itching are not uncommon with both human and purified equine immunoglobulins. Published data indicate that immunoglobulins can be safely injected into already infected animal bite wounds following proper wound cleansing and the administration of appropriate antibiotics.

Equine rabies immunoglobulin

Most ERIGs that are manufactured presently are highly purified and the occurrence of adverse events has been significantly reduced. Unlike the original unpurified rabies antisera which resulted in adverse reactions in as many as 40% of recipients, the adverse-reaction rate of patients receiving highly purified ERIGs has been reduced to <1–2%. Serious adverse reactions, including anaphylaxis, may occur in spite of a negative skin test. ERIG should only be used by medical staff trained and equipped to manage such an adverse reaction. Unpurified rabies antisera are not recommended.

F(ab´)2 products

F(ab´)2 fragments are obtained by cleavage of the immunoglobulin by a proteolytic enzyme, pepsin, followed by separation of the F(ab´)2 fragments from the Fc fragment. Many of the ERIGs now available are produced in this way. F(ab´)2 fragments are cleared more rapidly in vivo than intact immunoglobulins. Undesirable side-effects are rare and are similar to those listed above for ERIGs.

Human rabies immunoglobulin

HRIG produced under good manufacturing practices is virtually devoid of serious adverse reactions. It is purified from carefully selected donors, and processing eliminates viral contaminants including those of the human immunodeficiency and hepatitis viruses.

Purified cell-culture and embryonated egg rabies vaccines

These vaccines have not been causally associated with serious adverse effects. Mild serum sickness-like and urticarial reactions have been occasionally been Observed following booster doses of human diploid cell vaccine.

Guide for post-exposure prophylaxis
General considerations

The recommendations given here are intended as a general guide. It is understood that, in certain situations, modifications of these recommendations may be warranted. Such situations include, but are not limited to: exposure of infants or mentally disabled people to a suspect or confirmed rabid animal; and when a reliable exposure history cannot be ascertained, particularly in areas where rabies is enzootic, even when the animal is considered to be healthy at the time of exposure. A careful risk assessment should be conducted by a qualified medical professional on every patient exposed to a potentially rabid animal . Post-exposure prophylaxis consists of local treatment of the wound, initiated as soon as possible after an exposure, followed by the administration of passive immunization, if indicated, and a potent and effective rabies vaccine that meets WHO criteria . Post-exposure prophylaxis may be discontinued if the animal involved is a dog or cat that remains healthy for an observation period of 10 days after the exposure occurred; or if the animal is humanely killed and proven to be negative for rabies by a reliable diagnostic laboratory using a prescribed test. If the animal inflicting the wound is suspected of being rabid and is not apprehended, post-exposure prophylaxis should be instituted immediately.

When animal bites occur in a rabies-free area where adequate rabies surveillance is in effect, post-exposure prophylaxis may not be required depending upon the outcome of a risk assessment conducted by a medical expert knowledgeable in the epidemiology of rabies in the area and the proper requirements for assessing the risk involved . In areas where canine or wildlife rabies is enzootic, adequate laboratory surveillance is in place, and data from laboratory and field experience indicate that there is no infection in the species involved, local health authorities may not recommend anti-rabies prophylaxis.

Local treatment of wounds

Elimination of rabies virus at the site of the infection by chemical or physical means is an effective mechanism of protection. Therefore, the Consultation emphasized the importance of prompt local treatment of all bite wounds and scratches that might be contaminated with rabies virus. Recommended first-aid procedures include immediate and thorough flushing and washing of the wound for a minimum of 15 minutes with soap and water, detergent, povidone iodine or other substances of proven lethal effect on rabies virus. If soap or an antiviral agent is not available, the wound should be thoroughly and extensively washed with water. People who live in rabies-infected areas should be educated in simple local wound treatment and warned not to use procedures that may further contaminate the wounds. Most severe bite wounds are best treated by daily dressing followed by secondary suturing where necessary. If suturing after wound cleansing cannot be avoided, the wound should first be infiltrated with passive rabies immunization products and suturing delayed for several hours. This will allow diffusion of the antibody to occur through the tissues before suturing is performed. Other treatments, such as the administration of antibiotics and tetanus prophylaxis, should be applied as appropriate for other bite wounds.

Administration of rabies biologicals for passive immunization

The role of passive rabies immunization products is to provide the immediate availability of neutralizing antibodies at the site of the exposure before it is physiologically possible for the patient to begin producing his or her own antibodies after vaccination. Therefore, passive immunization products should be administered to all patients presenting with exposure to rabies-infected material onto mucous membranes or into transdermal wounds.

Classes of rabies biologicals and precautions for their use

There are three classes of rabies biological products for passive immunization available at present: human rabies immunoglobulin (HRIG); equine rabies immunoglobulin (ERIG), and highly purified F(ab´)2 products produced from ERIG. Most ERIG products currently being manufactured are highly purified and the occurrence of adverse events has been significantly reduced. Given that the clearance of F(ab´)2 fragments is more rapid than intact immunoglobulins, the Consultation recommended that in cases of multiple severe exposures, HRIG should be used for passive immunization. Most of the new ERIG preparations are potent, highly purified, safe and considerably less expensive than HRIG. However, they are of heterologous origin and carry a small risk of hypersensitivity reactions and therefore a skin test should be conducted prior to administration of ERIG and F(ab´)2 products according to the guidelines of the manufacturer. Serum sickness, using a highly purified ERIG product, appears among <1–2% of recipients and usually develops 1 week after administration. In the event of a positive skin test to ERIG or an F(ab´)2 product, HRIG should be administered. If HRIG is not available, ERIG or F(ab´)2 products should still be used but should be administered under the close supervision of competent staff located in adequate medical facilities.

Dosage and administration

The dose for HRIG is 20 IU/kg body weight, and for ERIG and F(ab´)2 products is 40 IU/kg body weight. As much of the recommended dose of passive immunization products as is anatomically feasible should be infiltrated into and around the wounds. Multiple needle injections into the wound should be avoided. If a finger or toe needs to be infiltrated, care must be taken not to cause a compartment syndrome, which can occur when an excessive volume is infiltrated under pressure and blood circulation is impaired. In the event that a remainder of passive rabies immunization product is left after all wounds have been infiltrated, it should be administered by deep intramuscular injection at an injection site distant from the vaccine injection site. Animal bite wounds inflicted can be severe and multiple, especially in small children. In such cases, the calculated dose of the passive rabies immunization product may not be sufficient to infiltrate all wounds. In these circumstances, it is advisable to dilute the passive immunization product in normal saline to a sufficient volume to be able to inject all wounds. A full course of vaccine should follow thorough wound cleansing and passive immunization.

Vaccine administration for active immunization

Intramuscular regimens

A limited number of rabies vaccines are considered thus far to be safe and efficacious for post-exposure prophylaxis when administered by the intradermal route in two different regimens. Evaluation of these products by this and previous WHO meetings of rabies experts is mostly based on a review of published articles (in peer-reviewed journals) on clinical studies (on safety, immunogenicity and efficacy) conducted with these products and an analysis of results of laboratory tests (e.g. RFFIT, FAVN test, NIH test) carried out as part of these studies by independent laboratories, including WHO collaborating centres, by national control authorities and/or by the manufacturers. WHO does not conduct laboratory tests.

Cell-culture or purified embryonated egg rabies vaccines having a potency of at least 2.5 IU per single intramuscular immunizing dose should be applied according to one of the following regimens. Five-dose intramuscular regimen (Essen regimen) One dose of vaccine is administered intramuscularly on days 0, 3, 7, 14 and 28. Injections must be given in the upper arm (deltoid region) or, in small children, into the anterolateral thigh muscle. Vaccine should never be administered into the gluteal region, where absorption is unpredictable.

Abbreviated multisite intramuscular regimen (“2–1–1” or Zagreb regimen) One dose of vaccine is administered intramuscularly into the left and one into the right upper arm (deltoid region) on day 0 followed by one dose into the upper arm (deltoid region) on days 7 and 21. This schedule saves two clinic visits and one vaccine dose.

Intradermal regimens

A limited number of rabies vaccines has been recognized to date by WHO as safe and efficacious for post-exposure prophylaxis when administered by the intradermal route in two different regimens. Local manufacturers in rabies endemic countries are beginning to produce rabies vaccines. The intradermal use of these vaccines should be based on adherence to WHO requirements for that route and approval by national health authorities . New vaccine manufacturers should provide clinical evidence that their products are immunogenic and safe when used intradermally. Clinical evidence should include clinical trials involving a vaccine of known immunogenicity and efficacy when used by this route as control, serological testing with rapid fluorescent focus inhibition test, and publication in internationally peer-reviewed journals.

Updated Thai Red Cross intradermal regimen (“2–2–2–0–2” regimen) Sufficient clinical evidence was presented to the Consultation indicating that a single dose of vaccine given on day 90 of the original Thai Red Cross regimen (“2–2–2–0–1–1” regimen) can be replaced if two doses of vaccine are given on day 28 (“2–2–2–0–2” regimen). The Thai Red Cross regimen considerably lowers the cost of vaccination as the total volume of vaccine required is much less than that needed for intramuscular regimens.

The schedule for the updated Thai Red Cross intradermal regimen is as follows: one dose of vaccine, in a volume of 0.1 ml is given intradermally at two different lymphatic drainage sites, usually the left and right upper arm, on days 0, 3, 7 and 28. Vaccine administered intradermally must raise a visible and palpable “bleb” in the skin. In the event that a dose of vaccine is inadvertently given subcutaneously or intramuscularly, a new dose should be administered intradermally. Currently there are two vaccines that have been proven to be efficacious in the Thai Red Cross regimen: purified Vero cell rabies vaccine produced by Aventis Pasteur and purified chick embryo cell rabies vaccine produced by Chiron Vaccines.

Eight-site intradermal regimen (“8–0–4–0–1–1” regimen) One dose of 0.1 ml is administered intradermally at eight different sites (upper arms, lateral thighs, suprascapular region, and lower quadrant of abdomen) on day 0. On day 7, four 0.1 ml injections are administered intradermally into each upper arm (deltoid region) and each lateral thigh. Following these injections, one additional 0.1 ml dose is administered on days 28 and 90. This regimen lowers the cost of vaccine administered by intramuscular regimens and generally produces a higher antibody response than the other recommended schedules by day 14. It does not result in a significantly earlier antibody response and in order to ensure optimal treatment, a passive immune product must be administered to patients presenting with severe exposures. Only two commercial products are today considered safe and efficacious when administered according to this regimen. They include a human diploid cell vaccine produced by Aventis Pasteur and a purified chick embryo cell rabies vaccine produced by Chiron Vaccines. Intradermal injections must be administered by staff trained in this technique. Vaccine vials should be stored between 2 ºC and 8 ºC after reconstitution and the total content should be used as soon as possible, but at least within 8 hours. Rabies vaccines formulated with an adjuvant should not be administered intradermally.

Post-exposure prophylaxis of previously vaccinated people

Individuals who are not immunocompromised and who have been previously vaccinated with a potent and effective rabies vaccine that meets WHO criteria for vaccine production and have adequate documentation should receive a two booster series consisting of one intramuscular or intradermal dose on days 0 and 3. The administration of passive immunization is not required. Local wound treatment should be completed as noted above. People who have received pre-exposure or post-exposure vaccination using a vaccine of unproven potency, should receive a full post-exposure vaccination series including passive immunization.

Post-exposure prophylaxis of HIV-infected people and HIV/AIDS patients

Several studies of patients with HIV/AIDS have reported that those with very low CD4 counts will mount a significantly lower or no detectable neutralizing antibody response to rabies. In such patients and those in whom the presence of immunological memory is no longer assured as a result of other causes, proper and thorough wound treatment as described above and antisepsis accompanied by local infiltration of a passive immunization product are of utmost importance. Immunocompromised patients with category II exposures should receive rabies immunoglobulin in addition to a full post-exposure vaccination series as listed above. An infectious disease specialist with expert knowledge of rabies prevention should be consulted.

Table No: 1, should serve as a guide for post-exposure prophylaxis. In cases where exposure is questionable or a patient has a concurrent medical condition that may complicate post-exposure prophylaxis, an expert in the administration of rabies prophylaxis should be consulted.

Table No : 1
Type of contact, exposure and recommended post-exposure prophylaxis

Important :

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

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

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

4. Post-exposure prophylaxis should be considered when contact between a human and a bat has occurred unless the exposed person can rule out a bite or scratch, or exposure to a mucous membrane.