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Persons bitten by an animal usually suffer great pain and anxiety. Everyone, of these patients try to get the best possible treatment available to them, under the circumstances. In their efforts to get relief they surrender completely to their doctors and hope for the best. Doctors always try to provide the best possible treatment available under the circumstances, to their patients. This intention of providing the best possible treatment is limited by the Level of Knowledge, Professional Skill, and the Availability of Resources. The Resources are the products to be used and the facility for providing the care. The knowledge of the doctors, in general, and specifically in the field of management of animal bites, depends on the information disseminated by the Pharmaceutical companies, marketing various products used in the treatment of animal bites. The Text Books on Preventive and Social Medicine [Now called Community Medicine], Internal Medicine, and Microbiology. The WHO, and the NICD guidelines. The Scientific Articles published in various Medical Journals. The Information provided by the Web sites of various organizations like WHO, CDC, NICD, APCRI, etc. The information from Pharmaceutical companies can sometimes be misleading. A few important lines discarded from a text changes the intended message of the text. The authors might have tried to convey a different message, but the persons deleting some selected lines from the text can change the message to suit their purpose. The Text Books on PSM or Community Medicine, Internal Medicine, and Microbiology do not always provide the most recent information. The WHO, CDC, NICD and APCRI guidelines provide very recent information. The articles published in different medical journals express the view point of the authors only. These views mayor may not be accepted by all very knowledgeable persons. The very aggressive sales promotion of the different Pharmaceutical companies has caused the evolution of many controversies in the Post-exposure management of Animal Bites. Many are trying to promote their products based on half truths. Some are even using the scientific papers providing results obtained by using different products as the results obtained by using their products of near similar nature. The Results of Studies made on one product being falsely claimed by others as the virtues of their product. Some of the recommendations of the WHO do not seem to have relied on Hard Scientific Evidence, but on Theory. This has created some controversy in the minds of persons who think deeply and do not necessarily rely on chance for survival of their patients. Incorrect information has been spread about the storage of the products. All vaccines and immunoglobulins require cold chain for storage and transportation. Some companies are mentioning about the stability tests done in the Quality control Labs for checking the stability of the lyophilised product as a virtue of their product thereby creating a controversy. However, the World Health Organization, Expert Consultation on Rabies, Technical report series 931, mentions that "WHO wishes to alert procuring UN agencies that the improper storage, handling and transportation of vaccines may affect their quality, efficacy and safety". 1 Some of the controversies are due to incorrect information about the approved products. An Avian Embryo Vaccine being promoted as a TCV. An indigenous HDCV is being promoted as the HDCV mentioned in the Text Books of Medicine. Incorrect information has also been disseminated about the Tumorigenicity of PVRV. Incorrect information has also been spread regarding Life long immunity conferred by some vaccine. The PDEV is not a cell culture vaccine. It is an Avian Embryo Vaccine. However, it is administered 1M like the TCVs. It is a modern Rabies vaccine. It has not been found suitable for IDRV in the ICMR study. As per WHO the product available in India is not the same product which was approved by WHO. The technology is the same, but the plant is new and in a different place. The product has to re-establish itself. All the HDCVs in the world are not the same. The HDCV mentioned in the Text Books of Internal Medicine was the first successful TCV. It was manufactured by Merieux. The HDCV available in India at present is manufactured by SII. It is available in liquid form, as well as in the lyophilized form. The liquid form comes with an adjuvant and has Thiomersal as a preservative and it is not suitable for ID usage. This vaccine is a new product and has to establish itself. In INDIA, at present, four different PVRVs are available. All the four PVRVs are not the same. The absence of tumorigenicity and the absence of any viral, bacterial or mycoplasmic contamination in the PVRV manufactured by Sanofi Pasteur have been confirmed by the safe use of 70 million doses of the product since launch in 1988. No Vaccine confers Life Long Immunity against Rabies. The HDCV from Sanofi Pasteur is being used for 29 years, PCEC from Novartis Vaccines is being used for 21 years, and PVRV from Sanofi Pasteur is being used for nearly 20 years, these are the products in use for the longest duration. At present there cannot be any claim of life long immunity, as it cannot be sustained by hard facts. The WHO TRS 931 mentions about certain criteria being followed by the WHO in recommending a particular vaccine or schedule as safe for use in PEP It mentions about clinical evidence being essential for all Vaccines to be accepted as safe and immunogenic. For acceptance, clinical trials of the new vaccine should have an accepted vaccine as control. The serological testing should be with RFFIT, and the study should be published in internationally peer reviewed journals. 1 The WHO TRS 931, also mentions that Persons previously vaccinated with a potent and effective rabies vaccine (that meets WHO criteria) and have adequate documentation should receive a two booster series consisting of one 1M or ID dose on day o and, another on day 3. Passive immunization with RIGs is not required for persons who have taken a full course of vaccination with TCVs and then having are-exposure. Not all, the vaccines approved for PEP are having Hard Scientific Evidence of Studies in Re-exposure patients, published in Internationally peer reviewed journals. Surprisingly in the Guidelines for the management of Re-exposure cases, all vaccines approved for PEP are having the same dosage schedule. For acceptance of a Vaccine, for use in PEp, hard scientific evidence of clinical trials having an accepted vaccine as control and the study published in internationally peer reviewed journals is essential. But, surprisingly for the Guidelines on management of Re-exposure cases, no such Hard Scientific Evidence was essential, for a 100% fatal disease. The Safety and Immunogenicity of various regimens in Post exposure prophylaxis is well established. For 1 year in all cases [registration requirement]. For 3 Years in some cases [study reports]. There is no scientific evidence so far for Long term Immunogenicity [greater than 3 years] in PEP studies. My querry is that if seroprotection is well established then why even 2 doses after re-exposure in at least in those cases reporting within 3 years of the full course of vaccination. From literature we could get information about good and poor immune responders. Does the phenomenon of Good and Poor responders exist? The WHO TRS 931 mentions Pre-exposure vaccination consists of a full dose of vaccine given by 1M or 0.1 ml given ID on days 0, 7, 21 or 28. If the immune status of a patient is doubtful, then the immune response to the vaccine should be assessed after the 3 dose pre-exposure series has been administered. Periodic boosters are required for people who are at continual risk. The Persons at continuous risk are people who work with live rabies virus in a diagnostic or research laboratory or in vaccine production, rabies researchers, diagnostic laboratory workers (where virus is present continuously, often in high concentrations, and where specific exposures are likely to go unrecognized). Serological testing is to be done every 6 months. A booster is required if the titre falls below 0.5 IU/ml. Pre-exposure vaccinated persons are to get only 2 Boosters, one on day 0 and day 3 in reexposure cases. And Yet, Surprisingly, no periodic boosters or getting the titres checked by RFFIT have been recommended for the general category of patients getting pre-exposure vaccination. Reviewing scientific literature I could gather very interesting information. The review of the Medical Literature on the topic of Boosters for re-exposure reveals that there are a lot of grey areas. There is a possibility of poor immune responders in about 25% of the population. Patients do not come to their doctors, with labels about their immune status attached, to them. There is every possibility of poor immune responders succumbing to Rabies in a re-exposure case. Fortunately most dogs are not Rabid. Even'if a rabid dog bites a person, there is only 56% possibility of the victim succumbing to Rabies. Many persons are surviving because of this factor. Some times the Second exposure is more serious than the first. It is very risky for a doctor to depend on the theory of Amanmesis. In long duration Pre-exposure Vaccination studies, there are evidence of Good and Poor immune responders. 3&4 There are not many well documented long term studies in Re-exposure cases. A prospective study carried out in Thailand, followed the immune response in 118 patients given a twodose 0.1 milD booster of PVRV on DO and D3 after having been given eitherpre-(n=38) or post-exposure (n=80) rabies vaccine 5 to 20 years previously. Of these subjects, 109 had received PVRV and 9 had received HDCV as primary vaccination. Antirabies GMTs on days 5,7 and 14 after boosting showed a good anamestic response. All volunteers had detectable (= 0.03 IU/mL) neutralizing antibodies on day O. Only one had an antibody titer < 0.5 IU/mL on day 7 (0.48 IU/mL). That was a 75 year old female who had received an ID postexposure series of PVRV 10 years previously, but her titer was 6.25 IU/mL by day 14. This study supports current recommenda-tions that immunity is long lasting and that boosters without immunoglobl,llin are sufficient even when prior vaccination was more than 5 years previously. Taking the case of the lady in that study, who had an antibody titre < 0.5 IU/mL on day 7. If the reexposure was by a confirmed rabid animal, then she could have succumbed to rabies, because she had circulating antibodies in the protective range only after 7 to 14 days after the re-exposure. This interval of time would have been sufficient for the rabies virus to get entry into the nervous system. Once the rabies virus gets entry into the nervous system, the circulating antibodies cannot prevent the patient from succumbing to rabies. In my long and vast clinical experience in treating animal bite cases, I have come across some cases where the circulating antibody titres to the rabies virus was not detectable [ < 0.3 IU/mL] even six months to two years after taking full course with TCV in ESSEN schedule. The second exposure was of a very serious nature, by a suspected rabid animal and potentially life threatening.6 All measures had to be taken to save the patients from imminent death due to rabies. Fortunately most animals are not rabid and this is the reason why we have not heard of treatment failures in re-exposure cases. There are two factors involved for a treatment failure to occur in a reexposure case. The patient should be a poor immune responder and the animal causing the exposure should be rabid. Only after determining the Rabies Virus Neutralising Antibody Titre, 14 days after completion of both pre and post - exposure vaccination with TCVs can we be sure that the primary course of vaccination was successful, if the titre was> 0.5 IU/ mL of serum. In re-exposure cases of animal bites the schedule of only 2 doses, one each on D 0 and D 3, holds good if the primary course of vaccination was successful. Otherwise the re-exposure case should be treated as a fresh case with full course of TCV + RIG. Or, after 7 days of a 2 booster series the titre should be checked by RFFIT. While accepting the theory of Anamnestic response there is a need to have enough Immunological data to support the Hypothesis. Then only, we will be confident enough to change our practice of advising full course after 5 yrs (best solution can be the study like pre-exposure booster study). If we could trace back previously immunised subjects (5 or 10 yrs back) and study their Titers at Day 0 and 14 days after a Day 3 dose to observe their Seroprotection status, then it would be a sound basis for such a recommendation. A prospective follow up study on patients receiving full course PET is needed.
References
This paper was presented by the author at the APCRICON 2006 held at Jammu, on 7'" July 2006. Address for communication with the author: Dr. Amlan Goswami, 28-A, Gariahat Road, Flat-2A, 2nd Floor, Kolkata-700029. INDIA. E-mail: amlan_koIkata29@rediffmail.com
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