Dr. Amlan Goswami, Editor - APCRI
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The 4th annual meeting of the Asian Rabies Expert Bureau (AREB) was held at Bangkok from 5th September 2007 to 7th September 2007. The Asian Rabies Expert Bureau (AREB) is an informal network of experts in rabies, and its members are from nine Asian countries (Bangladesh, China, India, Indonesia, Pakistan, Philippines, Sri Lanka, Thailand, VietNam). The focus of the meeting was on solutions for bringing down the death toll from Rabies in Asia. Two Asian countries, the Philippines and India have announced their goal of eliminating rabies by 2020, which means eliminating rabies in dogs. However, according to the conclusions of the 4th AREB meeting, the number of human deaths can and should be reduced as soon as possible, since human rabies deaths can be prevented even before rabies is controlled in dogs. Although it is 100% fatal, rabies is 100% preventable through prompt medical care for animal bite victims. Rabies post-exposure prophylaxis (PEP) More than 10 million people worldwide receive postexposure prophylaxis (PEP) each year after being exposed to rabies-suspect animals. Most of them live in the nine Asian countries currently represented in AREB (Bangladesh, China, India, Indonesia, Pakistan, the Philippines, Sri Lanka, Thailand and Viet Nam). PEP when administered in time and correctly (Le. according to WHO guidelines) is a very effective method of preventing the development of rabies in an exposed individual. PEP comprises of three items: (a) immediate washing ofthe wound, (b) rapid administration of high quality rabies 'immunoglobulins (RIG) by trained personnel for severe cases, and (c) a complete course of rabies immunization with modern cell culture vaccines. The vaccination course needs to comply with WHO recommended schedules, even if it takes several weeks to complete. Unfortunately PEP is not always applied in an optimal way. This puts lives at great risk. Efficient rabies PEP depends on many factors: (a) an educated population that knows what to do in the event of an animal-bite; (b) the availability of high quality biologicals (high quality and modern immunoglobulins and WHO prequalified cell culture vaccines), and (c) well-designed and well-equipped Animal-bite treatment centers with trained personnel that can provide adequate wound care, administer the treatment and maintain the cold chain necessary for the storage of biologicals. When a person has been bitten by rabies-suspect dog, a race against time begins. The rabies virus has to be eliminated or neutralised before it can reach the nervous system. Wound washing The rabies virus is present in the saliva of rabid animals and enters the human body through a bite, scratch or a lick over broken skin or intact mucosa. Thorough washing of the wound(s), by the bite victim himself/ herself or people around him/her, can eliminate or inactivate the virus and reduce the risk of infection. WHO recommends immediate and thorough flushing and washing of the wound for a minimum of 15 min with soap, detergent or iodine and water. If soap is not available, the wound should be extensively washed with water. This very basic step is often undervalued or ignored, when it should be considered as critical for the positive outcome of an exposed patient. The patient should then seek medical care at the closest hospital/clinic where animal-bite treatment is available to receive rabies vaccine and, in the case of severe exposure, rabies immunoglobulins (RIG). Rabies immunoglobulins (RIG) There are three classes of rabies biologicals currently available commercially for passive immunization: (a) human rabies immunoglobulins (HRIG), (b) equine rabies immunoglobulins (ERIG) and (c) the highly purified equine F(ab')2 products (pERIG). WHO recommends that immunoglobulins be infiltrated into and around the wounds in order to rapidly neutralise rabies virus at the inoculation sites before it reaches local nerve endings1,2 and remaining RIG, if there are any, should be injected intramuscularly (IM) at a site distant from the vaccine injection site. This reduces the viral load and immediately provides neutralising antibodies at the site of exposure before the patient begins producing his/her own antibodies after vaccination. The correct use of RIG requires a high level of skill. The body weight of the patient must be determined to calculate precisely the dose to be used. A higher dose may interfere with the production of antibody induced by vaccination. In the case of large or multiple wounds, RIG can be diluted to secure sufficient volume for correct infiltration of all the lesions. However, questions remain regarding how to assess the dosage of RIG needed for patients of low body weight, and current recommendations for dilution often result in a volume insufficient to correctly infiltrate all the wounds. Healthcare workers must also be informed that suturing of th~ wound, after infiltration of the RIG, should be delayed as long as possible, and be done no less than 2 h after RIG injection. Highly purified equine immunoglobulins (pERIG) are efficient, very well tolerated, and more affordable than HRIG. A recent retrospective study carried out in the Philippines on more than 7600 patients given pERIG (FavirabTM) between July 2003 and August 2005, showed a very low level of systemic adverse events « 1.5%); all resolved with no further complications. Although both WHO and the pERIG producers recommend a skin test to determine whether a patient will have a reaction to the product, AREB members agree that modern, high quality pERIG can and should be administered, under close supervision, even when the skin test is negative. AREB points out that the skin test is not really predictive, and is confusing for the health workers and patients. They suggest removing its recommendation from the pERIG product leaflet. In order to secure consistent quality, patient safety and treatment efficacy of RIG, the implementation of a WHO qualification process is required, since currently none exists, and only pre-qualified products should be candidates for use, with or without a skin test. Rabies vaccines Vaccination is the core of PEP. The WHO guidelines recommend the use of inactivated cell culture or purified embryonated egg vaccines5,6. Many countries are now making an effort to use only modem vaccines' a process which is hindered, of course, by unfavourable allocation of resources. More and more positive examples are being observed. In 2005, India stopped production of nervous tissue vaccines (NTV), which required many painful injections and had major side effects. Viet Nam, too, is in the process of switching from NTV to modem cell culture vaccines. NTVs, however, are still used in some countries, such as Pakistan. In order to decrease by a fraction the total cost of PEp, and ease the first steps of the switch from NTV to modern cell culture vaccines, several Asian countries have adopted the ID route of administration. This, however, should only be done with modern cell culture vaccines with a controlled potency per ID dose (to be defined by local regulations). Vaccine immunogenicity has to be documented from clinical trials. 10 injection of Vaccine must only be performed in specialized centres that treat a significant number of patients per day, with personnel trained to inject the vaccine in multiple sites via the intradermal route. It requires strict control of the conditions and duration of vaccine storage after reconstitution. Opened vials must be used within 8 h and kept at 5° C (±3° C) during that time. Specific care to avoid contamination of the vial should be taken when removing the successive ID doses since rabies vaccines do not contain preservative or antimicrobial components. Whatever vaccination route is used, patient compliance is essential and remains one of the main barriers to effective treatment. The observed lack of compliance in completing the treatment course is a problem, especially considering that, with ID schedules, a significantly lower immunogenicity is observed compared to IM schedules. Another issue identified by AREB is the mixing of IM and ID schedules. Even if a favourable outcome is occasionally reported when starting with dose 1 (and eventually dose 2) of the IM schedule, and then completing the treatment with an ID schedule, there is currently no recommendation or supportive data for these mixed schedules, and consequently they must be avoided as far as possible. Why does PEP fail? A review of cases considered as PEP failures showed that all (except one case of very severe multiple deep bites at the level of the head and neck), were due to deviations from recommendations. The deviations noted were (a) improper wound cleansing, (b) the absence of RIG administration, or (c) the noncompliance with the whole vaccination schedule. PEP failures have also been observed with the "Oxford" regimen ("the accelerated eight-site regimen") without RIG in cases of category III bites. Therefore, no one vaccination schedule can be considered as an alternative to RIG. These are all problems that need to be addressed in order to reduce the human rabies death toll. There is a need for proper and continuous training of personnel, especially when ID vaccination is performed; for sustained availability of good quality biologicals (modern RIG and WHO pre-qualified vaccines); for educating the public about the importance of immediate wound cleansing, rapid consultation at the dog-bite centre, and compliance with the entire vaccination schedule. Towards this, ARES is currently compiling basic recommendations for Animal-bite treatment centres, with a checklist of compulsory material and equipment. Rabies pre-exposure vaccination (PrEP) Many dog-bite victims do not receive PEp, or they receive it too late or it is incomplete. Many human deaths are due to the fact that RIG is often not administered because of unavailability or of its perceived cost versus the vaccine. Moreover, children 7" who .are the main victims of rabies - may not be treated because the exposure goes unreported. Pre-exposure prophylaxis (PrEP) can be a viable strategy in diminishing the number of rabies deaths, especially those resulting from unapparent or unreported exposures and delays in post -exposure prophylaxis. Dog-bite victims who have been previously fully immunized do not require RIG infiltration, and need only two booster injections of vaccine on D0 and D3. Rabies pre-exposure vaccination is recommended by WHO for people at high risk of exposure such as those working in rabies diagnostic or research laboratories, veterinarians, animal handlers, animal rehabilitators and wildlife officers. Since children have the highest risk of severe rabies exposure, WHO also promotes vaccination of children living in regions where canine rabies is highly endemic1. The Philippines has already launched a pilot pre-exposure vaccination campaign: 50,000 school children in highly endemic areas will be preventively vaccinated. The main limitation to generalized PrEP programmes in Asia is the belief that the public health cost will not be sustainable. However, a recent study comparing the cost of rabies PEP and PrEP in Thai children showed that both strategies cost the same when the dog-bite incidence is 2-30%, depending on which PEP treatment regimens are used. In regions with a high incidence of canine rabies and where rabies control in dogs is not yet achieved or not effective, improved PEP is a primordial requirement, but systematic PrEP of children should be considered in order to achieve a rapid decrease in human rabies deaths. Acknowledgements ARES acknowledges the great support of Sanofi Pasteur in helping to hold the meeting.
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