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From: TSS ()
CJD WATCH MESSAGE BOARD Pathogenesis and transfusion risk of transmissible spongiform encephalopathies. Brown P. NINDS/NIH, Bethesda MD, USA. paulbrown@comcast.net The genesis (and pathogenesis) of sporadic and familial forms of human transmissible spongiform encephalopathy (TSE) is unknown, but the disease process may originate spontaneously in the brain as a statistically random event involving misfolding and amyloid formation of the "prion" protein. The pathogenesis of environmentally acquired TSE depends on the route of infection and is likely to involve both neural and haematogenous paths of neuro-invasion. Blood infectivity is well documented in experimental rodent models of TSE and in natural scrapie infections, but has not yet been proved to occur in humans. The knowledge that many plasma pools have included donations from individuals who later died of sporadic Creutzfeldt-Jakob disease (sCJD), together with the failure to identify any affected recipients, implies that the risk is either negligible or absent. In sharp contrast, two out of 26 recipients of labile blood products from individuals who later died from the variant form of CJD (vCJD) have became infected, and the still-living at-risk recipients are under continuing surveillance. PMID: 16050152 [PubMed - in process] something even stranger, usda does not even much believe in the spontaneous BSE in cattle, or don't want to anyway. they are at a crossroads of having to believe it and stanley pushing his cdi test$$$ so for sure, they don't want to have to believe it. so why would it happen for sporadic CJDs??? PDF]Freas, William TSS SUBMISSION File Format: PDF/Adobe Acrobat - Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary Sr. [flounder@wt.net] Monday, January 08,200l 3:03 PM freas ... http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf Docket: 02N-0370 - Neurological Devices; Classification of Human Dura Mater Greetings, please be advised; with the new findings from Collinge et al; that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc, the commonest sporadic CJD, i only ponder how many of the sporadic CJDs in the USA are tied to this alternate phenotype? these new findings are very serious, and should have a major impact on the way sporadic CJDs are now treated as opposed to the vCJD that was thought to be the only TSE tied to ingesting beef, in the medical/surgical arena. these new findings should have a major impact on the way sporadic CJD is ignored, and should now be moved to the forefront of research as with vCJD/nvCJD. the USA has many TSEs, the USA lacks sufficient testing for TSEs in cattle, and the USA still refuses to rapid TSE test USA cattle in sufficient numbers to find, when the late Dr. Richard Marsh had proven that mink had gone down with a TSE (TME), from being fed on 95%+ downer cattle. the GAO has also warned the industry and the FDA that the ruminant-to-ruminant feed ban has to significantly improved if they expect to keep BSE/TSEs out of USA cattle. Scrapie has increased significantly, and CWD is spreading. all this should warrant CJD/TSEs in humans in the USA to be made reportable on a National bases, immediately... SNIP...FULL TEXT; http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be11.html https://web01.aphis.usda.gov/regpublic.nsf/0/eff9eff1f7c5cf2b87256ecf000df08d?OpenDocument ITEM 4 – EARLY PHASE OF vCJD INFECTION IN RECIPIENTS OF BLOOD TRANSFUSIONS (SEAC 87/3) 11. The Chair informed members that the Committee on Microbiological Safety of Blood Tissues and Organs (MSBTO) had requested SEAC advice. MSBTO asked whether a scientific distinction could be drawn between tissue/organ donors that have - - 6 received blood transfusions either a few days or up to a week before donation (recent blood recipients), or in the more distant past (historic blood recipients), in terms of the relative load of vCJD agent that might be present in bone, tissues or organs. A number of individuals receive blood transfusions shortly before they die and become tissue/organ donors. Thus, the question related to whether there is a significant risk of vCJD transmission associated with such blood transfusions for the recipient of the tissues or organs. The advice from SEAC would inform possible risk reduction measures under consideration by the MSBTO. A SEAC statement would be drafted on the basis of the discussion. 12. Dr Marc Turner (UK Blood Services and Co-Chair of the Bone and Tissue Subcommittee of the MSBTO) provided the background to the MSBTO request. Since the identification of two cases of probable blood transfusion associated transmission of vCJD, the Blood Services, on the advice of the MSBTO, have deferred blood donors who themselves have received blood transfusions. This measure was instituted to reduce the possibility that blood transfusions could contribute to a self-sustaining vCJD epidemic. 13. Dr Turner explained that the potential risks of vCJD transmission associated with cell/tissue/organ transplants had also been considered by a vCJD Subcommittee of the MSBTO. Deferral of cell/tissue/organ donors that had received a blood transfusion had been considered. However, in the case of donors of bone marrow, kidney, liver, heart and lung there are shortages. As the primary use is for gravely ill individuals, deferral would not be beneficial to patients. Therefore, for patients urgently in need of potentially lifesaving operations, deferral of donors of such tissues/organs would not be instituted. 14. Dr Turner explained that the balance between the potential vCJD transmission risks and patient benefits for transplants of other tissues/organs such as bone, tendons, ligaments, corneas, heart valves and skin was less clear. These tissues were mainly derived from cadaveric donors and submitted to tissue banks. The majority of these donors will have received blood transfusions around the time of death whilst a smaller number will have received historic blood transfusions. It may be possible to introduce deferral of historic recipients of transfusions without incurring tissue shortages. However, deferral of all donors that had received blood transfusions would incur shortages. MSBTO was seeking advice from SEAC on whether a scientific distinction could be made between recent and historic recipients of blood transfusions, in terms of potential risk of vCJD transmission from transplants. If so, - - 7 could a threshold of transmission risk, in terms of the time following transfusion for recent and historic transfusion recipients, be defined. 15. Members noted that there were very few data available to answer these questions. It was suggested that some distinction could be made between the current risk of transmission via a blood transfusion, and the historic risk prior to the introduction of precautionary measures such as leucodepletion and the restriction on recipients of blood transfusions from donating blood. It was noted that measures such as leucodepletion reduced, but did not eliminate infectivity in blood. 16. One member noted that two papers by Beringue et al.1 that describe early accumulation of PrPres in the spleen of mice following intraperitoneal inoculation with scrapie complemented the data presented in SEAC paper 87/3. In the studies, PrPres was detectable in the spleen within one hour post-inoculation, increased to a peak at 4 hours, decreased at 6 hours and was undetectable from 12 or 24 hours before increasing again at between 5 and 7 days post-inoculation. Although the timing of PrPres accumulation in these studies differed compared with the reports presented in SEAC paper 87/3, this was probably due to strain specific differences in incubation time. It was noted that most of the inoculum would accumulate, not in the spleen, but in the liver and lung following injection. 17. Members asked whether the increase in splenic PrPres in the first few hours post-inoculation reported in the studies by Beringue et al. (2000) was due to accumulation of the inoculum or replication. Members were informed that the increase was thought to be due to accumulation of the inoculum. The inoculum was possibly then degraded before replication subsequently allowed the agent to be detected again almost a week later. Another member explained that although it was not possible at present to definitively distinguish between agent accumulation and replication, on-going work at the Institute of Animal Health lent support to this suggestion. Studies to differentiate between these two processes were underway. It was likely that the timing of these processes would differ between different strains of agent. 1 Beringue et al. (2000) Pharmacological manipulation of early PrPres accumulation in the spleen of scrapie-infected mice. Arch. Virol. Suppl. 39-56. Beringue et al. (2000) Role of spleen macrophages in the clearance of scrapie agent early in pathogenesis. J Path. 190, 495-502. - - 8 18. One member noted that in most of the animal studies under consideration, brain homogenate had been used as the inoculum. The infectious agent in such preparations was likely to be in a more aggregated form than when endogenously produced in human blood. Accumulation of a more aggregated form of a prion agent by the liver, lung and spleen would be relatively more efficient. 19. In response to a question about the level of infectivity in the blood of rodent models, members were informed that no studies have examined the period immediately following inoculation. Infectivity was difficult to detect in rodent blood. 20. It was noted that the findings from animal models suggest that there may be windows of increased or decreased risk within the first week following transfusion. However, members considered that the data available were too limited, and could not be directly applied to define windows of lesser or greater transmission risk from human tissue/organ transplants. 21. It was suggested that, on the basis of the evidence available, the prion agent would have insufficient time to replicate in recipients of a recent, compared with a historic, blood transfusion. Thus, the transmission risk following transplantation of a tissue/organ from a historic transfusion recipient could be higher than from a recent transfusion recipient. 22. In view of the large proportion of the inoculum sequestered by the liver, lung and spleen, a member asked whether other tissues/organs could be relatively free of the inoculum. Members considered that in the early phase of prion infection following intravenous administration, the tissue infectivity levels would correlate with the blood supply to, and blood content of, tissues. In contrast to times much later in the incubation period, no distinction could be made between tissues of the lymphoid and central nervous system and other types of tissue in terms of infectivity levels. Thus, in the early period following a transfusion with infected blood, highly vascularised organs such as the liver, lung and spleen, as well as bone would be more likely to carry infectivity. Thus, a distinction could be made between tissues that are highly vascularised and those that are not, in terms of potential infectivity levels within the first week following blood transfusion. 23. In response to a question about the turnover of tissues in tissue banks, Dr Turner explained that it was dependent on tissue type. For example, turnover of heart valves was relatively small but - - 9 turnover of corneas was larger because they can only be stored for a short time. Members suggested that data on the turnover or lifetime of tissues in tissue banks could be used in conjunction with information on the timing of measures to protect the blood supply to make some assessment of the relative risks posed by the use of specific types of tissues/organs. 24. Members asked whether it was possible to screen tissue/organ donors for markers of infection. Dr Turner explained that in principal, it would be possible to analyse tonsillar and splenic samples from cadaveric donors for the presence of PrPSc before tissues were used. However, the time taken for tests precluded screening of donors before the use of some tissues with a short ex vivo lifetime such as organs and corneas. A feasibility study for the screening of cadaveric donors was under consideration. One member suggested that retrospective screening of donors would also help to inform assessment of transmission risks but noted that ethical considerations would influence such a strategy. Dr Turner indicated that such strategies were under consideration but the associated ethical issues raised difficulties. 25. Given tissue infectivity levels in the very early stage of infection are likely to be associated with blood, members asked whether it was possible to wash tissues to remove blood and therefore infectivity. Dr Turner explained that solid organs are perfused, but that even after perfusion organs are likely to contain significant quantities of residual blood. Tissues such as tendons and heart valves are stringently cleaned. The UK Blood Services are currently investigating processes to remove the blood and bone marrow from bone. The committee considered that it was important to investigate processes that would efficiently remove blood and bone marrow from bone but noted that some processes may damage the integrity of the bone itself. The committee noted that SEAC had advised previously to avoid pooling of tissues, such as bone, which reduces transmission risks by ensuring a one to one relationship between donor and recipient, preventing possible multiple transmissions. - - 9 26. Members questioned the large numbers of cadaveric donors that are transfused before death, asking whether all such transfusions were necessary. Dr Turner indicated that a review of the use of blood was underway, however blood transfusions were normally conducted to manage underlying medical conditions. In the past, some donors had been transfused with blood prior to donation to induce an immunologically suppressive effect, increasing the - - 10 success of transplantation. More sophisticated methods to suppress the immune system are now used. 27. Members considered that, because of a small background risk of vCJD infection in the population as a whole, tissues/organs from donors that had not received a blood transfusion carried some risk of vCJD transmission. It was noted that recipients of blood products from vCJD cases had been notified and deferred from tissue/organ donation. All recipients of tissues/organs were also deferred from blood transfusion. A member considered that it would be important to provide to potential tissue/organ recipients clear information on the risk of vCJD transmission via the transplant relative to the risks and benefits of undergoing surgery. 28. Members noted that, until sensitive ante mortem tests, especially for blood, became available it may not be possible to conduct definitive experiments that would further inform assessment of the transplant associated risks of vCJD transmission. 29. In summary, the committee concluded that: • current transmission risks associated with blood transfusion are lower compared with historic risks prior to the introduction of precautionary measures to reduce potential prion infectivity in blood. • on the basis of the very limited evidence available it is unlikely that significant replication of PrP will have occurred in the first week following a transfusion with infected blood. • tissue infectivity levels in the first week following transfusion with infected blood will be related to the blood supply to tissues. Thus, a distinction may be made between highly vascularised tissues and other tissues in terms of their potential infectivity levels within the first week following blood transfusion. • if possible, screening of cadaveric donors for the presence of abnormal PrP prior to transplantation, washing tissues/organs to remove blood before their use, and avoiding the pooling of tissues, may reduce transplant associated transmission risks. Limiting the numbers of unnecessary blood transfusions would also reduce risk. • a balance must be struck between the small increased risk of prion transmission by transplantation, and the benefits to patients receiving a transplant, especially where tissues/organs are scarce and are required for potentially life-saving procedures. It would be important to explain the risks and benefits to potential recipients of tissues/organs. http://www.seac.gov.uk/minutes/final87.pdf TSS #################### https://lists.aegee.org/bse-l.html ####################
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