Heterogeneous transfusion risk linked to variant Creutzfeldt-Jakob disease in a non-human primate model, Singeltary Review
Jessica Rontard,Jacqueline Mikol,Florian Almela,Daisy Bougard,Christelle Jas-Duval,Olivier Andreoletti,Jérôme Delmotte,
Mohammed-Amin Madoui,Jean-Philippe Deslys,Emmanuel E. Comoy
Published: November 10, 2026
https://doi.org/10.1371/journal.ppat.1014769
Abstract
Among the 178 cases of variant Creutzfeldt-Jakob disease (v-CJD) in the UK, three were reported between 2003 and 2007 to be linked to a probable transmission through blood transfusion. With no further primary or iatrogenic cases observed worldwide since 2016, several countries are lifting – or have already lifted - deferrals for blood donors who have lived in the UK or, more broadly, Europe, to reduce the threat of supply shortages. However, the high prevalence of silent infection according to abnormal PrP in lymphoid tissues (potentially 100 times higher than for clinical cases in the UK) remains a concern in assessing the potential iatrogenic risk associated with long-term silent carriers for a disease whose incubation periods can extend over decades. In the present study, after experimental intravenous contamination of cynomolgus macaques with v-CJD prions, a relevant model of the human disease, we observed a highly heterogeneous intra- and inter-individual distribution of apparent peripheral prion replication in lymphoid organs that appears to correspond largely to the prion load in blood, the highest levels of which are detectable by amplification-based detection assay. In addition, several primates have developed unexpected incomplete prion phenotypes that escape diagnosis by current conventional techniques and could be intravenously transmitted to mice in the absence of a functional immune system. The peculiar prion strains associated with these atypical phenotypes would involve peripheral mechanisms independent of the immune system, different from those of v-CJD. According to our observations, conventional lymphoid organ prevalence studies may underestimate the true extent of healthy v-CJD carriers, and blood transmission risk assessment should not be based on epidemiological data alone.
Author summary
Variant Creutzfeldt-Jakob disease (v-CJD) is considered a transfusion-transmissible infectious agent. In the absence of cases since 2016, several countries are lifting geographical restrictions on blood donation to reduce supply shortages. However, appendix studies have revealed a high prevalence of silent infection that questions the iatrogenic risk associated with long-term carriers (incubations extend over decades). Here, intravenously-contaminated macaques exhibited a highly heterogeneous distribution of v-CJD prion replication in lymphoid organs corresponding largely to the prion load in blood, whose highest levels are detectable by amplification-based detection assay. In addition, several primates developed incomplete prion phenotypes that escape diagnosis by current conventional techniques and could be intravenously transmitted to immunodeficient mice: the corresponding cryptic prion strains would involve immune-independent mechanisms, unlike v-CJD. According to our observations, the heterogeneity of peripheral prion replication observed in experimentally-infected macaques questions the actual prevalence of asymptomatic v-CJD carriers and the assessment of blood transmission-related risks in the human population.
snip…
These results suggest that the atypical prion strains linked to incomplete prion phenotypes and macaque myelopathy would not need a functional immune system to replicate before neuroinvasion after peripheral exposure, opposite to v-CJD. Either direct neuroinvasion may occur, as is partially the case in different immunodeficient models [49–51], or peripheral replication would occur elsewhere. This point has not yet been elucidated.
In conclusion, this study revealed that peripheral replication of v-CJD prions is widely heterogeneous and cannot be considered as an ultimate criterion for v-CJD diagnosis, whereas blood-related atypical prion strains rely on different peripheral mechanisms prior to neuroinvasion. At least three epidemiological consequences can be drawn here: (i) the prevalence of silent infected people might be wider than expected when using conventional techniques; (ii) the transfusion v-CJD risk would be limited to the highly infectious samples, which might be detected with current diagnostic techniques; (iii) atypical prions are uncontrollable with current techniques to date and would follow different pathophysiological mechanisms. As deferral measures are lifted in some countries, new tools are needed to analyze and circumvent these newly described novel prion strains.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014769
Opinion on the elimination of the leukocyte depletion step of plasma for fractionation collected in France Opinion on the elimination of the leukocyte depletion step of plasma for fractionation collected in France
Date du document : 26/06/2025 Date de mise en ligne : 17/07/2025
Although there is no European regulatory threshold or recommendation for residual leukocyte count regarding plasma for fractionation (PFF) intended for the manufacture of plasma-derived medicinal products (PDMP), France has recommended since 1998 a leukoreduction step requiring a residual leukocyte count of less than 1.0 x 106 per liter, for at least 90% of the production. The reason for this measure is related to the elective tropism for the lymphoid system of prions responsible for the variant form of Creutzfeldt-Jakob disease (vCJD). Leukocyte depletion of PFF is estimated to reduce their infectivity to prions by a factor comprised between 0.3 and 1 log10. With regard to this benefit, leukocyte depletion represents a significant constraint for PPF collectors, with in particular a very limited choice of suppliers of apheresis machines capable of filtering plasma with such performance, the impossibility of using mobile machines allowing collections at a distance from donation centers, a loss of raw material linked to the filtration stage and significant additional costs of PFF compared to the competition.
The High Council for Public Health (HCSP) has been asked whether it is appropriate to amend this regulatory requirement without compromising health safety in relation to prion risk. To support its opinion, the HCSP convened a working group comprising, in addition to members from the French Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM), the Etablissement français du sang (EFS) and the Laboratoire Français de Fractionnement et des Biotechnologies (LFB), a panel of prion disease specialists. The elements that were analyzed to form the basis of this opinion are based on epidemiological considerations concerning the "epidemic tail" of the vCJD episode, on a benefit-risk analysis of the elimination of the leukocyte depletion step, on a critical study of the effectiveness of the alternative methods claimed by the LFB to inactivate prions, on a probabilistic modeling work conducted within the working group to evaluate the safety impact of the elimination of the leukocyte depletion step in the manufacture of PFF, on a study conducted in Great Britain which led to the reintegration of British donors for the production of immunoglobulins and finally on the public health issue represented by the national "Ambition plasma" project intended to increase the health autonomy of France and Europe in the production of PDMP and in particular of immunoglobulins.
In light of all these elements, the HCSP decides on the advisability of eliminating the leukocyte depletion step during the manufacture of the 14 PDMPs manufactured by the LFB, whose residual infectivity threshold for prions, in a worst-case scenario, is considered negligible because it falls below the threshold of 0.01 50% infectious doses for each product administration. The HCSP ultimately recommends applying the current European standard for fresh frozen plasma to the PPF, i.e., a residual leukocyte count < 0.1 x 109 per liter for at least 90% of the production. The HCSP supplements this opinion with additional recommendations aimed at (i) using methodological approaches by the LFB in accordance with the current state of knowledge on prions for the evaluation of alternative methods to leukocyte depletion intended for prion inactivation, (ii) strengthening epidemiological vigilance with regard to the occurrence of new cases of vCJD or atypical cases of prion diseases, and (iii) re-evaluating the strategy mentioned in the opinion every 3-4 years to ensure its relevance. Furthermore, the HCSP reiterates the need to maintain the current leukocyte depletion requirements for labile blood products, including plasma for therapeutic use, as this measure is the only one capable of reducing a residual prion risk in these products.
Lire en français : Déleucocytation du plasma pour fractionnement collecté en France du 26 juin 2025
https://www.hcsp.fr/Explore.cgi/AvisRapportsDomaine?clefr=1441
https://www.hcsp.fr/explore.cgi/avisrapportsdomaine?clefr=1442
“The HCSP supplements this opinion with additional recommendations aimed at (i) using methodological approaches by the LFB in accordance with the current state of knowledge on prions for the evaluation of alternative methods to leukocyte depletion intended for prion inactivation, (ii) strengthening epidemiological vigilance with regard to the occurrence of new cases of vCJD or atypical cases of prion diseases, and…”
See;
https://bloodprp.blogspot.com/2025/07/opinion-on-elimination-of-leukocyte.html
Friday, July 18, 2025
Opinion on the elimination of the leukocyte depletion step of plasma for fractionation collected in France
https://bloodprp.blogspot.com/2025/07/opinion-on-elimination-of-leukocyte.html
https://bloodprp.blogspot.com/
THURSDAY, JANUARY 30, 2020
Docket Number: FDA-2012-D-0307 Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Draft Guidance for Industry Draft Guidance for Industry Singeltary Submission
''In the 2016 guidance, we recommended that prospective blood donors should be indefinitely deferred if they report having a blood relative with CJD. However, almost all cases reported are sCJD, not a genetic form of CJD. Blood relatives of individuals with sCJD are not at increased risk of developing the disease. The rare genetic forms of CJD (e.g., fCJD, GSS, FFI) share pathophysiological features with sCJD, and the transmission risk by blood components remains theoretical. Consequently, we recommend that establishments may stop asking prospective donors about having blood relatives with CJD.''
Greetings FDA et al,
I would again kindly like to comment on Docket Number: FDA-2012-D-0307, Docket Number: FDA-2012-D-0307 Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Draft Guidance for Industry Draft Guidance for Industry.
I still believe, that it is extremely dangerous to continue to base the safety of blood from the TSE Prion, by only believing the nvcjd only theory.
TSE Prion disease have expanded to other species i.e. the camel, and we now know that cwd and scrapie will transmit to pigs by oral routes.
Chronic Wasting Disease CWD TSE Prion in cervid has exploded across the USA, Canada, Mexico has now clue, Norway, Sweden, Finland, S. Korea, and we know that cwd is detected in the blood of cervid. CWD TSE Prion is highly infectious, and the risk factors from blood there from are very real.
we also know that all iatrogenic CJD is, is sporadic CJD, until the iatrogenic event is discovered, traced back, proven, documented in the academic domain, and finally the public domain, which very seldom happens due to lack of trace back efforts, thus, all iatrogeic events stay as sporadic cjd.
with the blood of cervid and cwd tse prion being detected there from, the science showing that cwd zoonotic potential is now real, the many different strains of cwd to date, with no real factor of how many different strains there are, with science now showing that indeed BSE, Scrapie, and CWD, both typical and atypical strains, showing scientific links to sporadic cjd, and that cwd in humans would would NOT look like nvcjd, but science shows that it would look like sporadic cjd, therefore, iatrogenic cjd from human cwd exposure is very real threat, i find these weakening of rules for blood risk factors from all the different strains of sporadic cjd very worrisome, especially now that officials are classifying vpspr, sgss, sffi, as sporadic cjd cases. we have no clue whether or not these are from iatrogenic events or not. this will be a foolish move if we put once again, corporate interest over human and animal health, but does not surprise me.
THIS will be very dangerous, and a foolish move for people who need blood, and for the medical and surgical theaters, and humans there from, and simply are not based on sound science imo, but are based on corporate greed.
WE KNOW now that the real statistics on human TSE Prion IS NOT one in a million, but data now shows that sporadic CJD, 85%+ of all human TSE Prion, the read statistics now show that those figures are one in 5,000. and sporadic cjd is NOT a single strain, but many, many, different strains, and the routes and sources are simply unknown.
NO WHERE IN SCIENCE LITERATURE HAS THE SPONTANEOUS CJD EVER BEEN PROVEN, without route and source, a happenstance of bad luck, this is simply wishful thinking$
TO weaken, instead of enhance and strengthen the risk of sporadic CJD tse prion from blood products by this Docket Number FDA-2012-D-0307 Recommendations, will only enhance the risk of TSE Prion to hemophiliacs, the medical and surgical arenas around the globe
yes, human tse prion are now 1 in 5,000. let that sink in.
snip…see full submission;
https://creutzfeldt-jakob-disease.blogspot.com/2020/01/docket-number-fda-2012-d-0307.html
THURSDAY, JANUARY 30, 2020
Docket Number: FDA-2012-D-0307 Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Draft Guidance for Industry Draft Guidance for Industry Singeltary Submission
https://creutzfeldt-jakob-disease.blogspot.com/2020/01/docket-number-fda-2012-d-0307.html
PLEASE SEE MORE in PDF download file
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recommendations-reduce-possible-risk-transmission-creutzfeldt-jakob-disease-and-variant-creutzfeldt
see full text submission here;
https://downloads.regulations.gov/FDA-2012-D-0307-0033/attachment_1.pdf
MONDAY, MAY 13, 2024
UK Parliament UIN 24699, tabled on 2 May 2024 BSE Disease Control Singeltary Submission
https://prpsc.proboards.com/thread/160/parliament-24699-tabled-2024-control
https://bovineprp.blogspot.com/2024/05/uk-parliament-uin-24699-tabled-on-2-may.html
Monday, May 20, 2024
INFECTED BLOOD INQUIRY THE REPORT MAY 20, 2024
https://bloodprp.blogspot.com/2024/05/infected-blood-inquiry-report-may-20.html
https://prpsc.proboards.com/thread/162/infected-blood-inquiry-report-2024
Risk of transmission of amyloid β pathology via transfused blood products
Author links open overlay panel Gargi Banerjee PhD a , Gustaf Edgren PhD b , Jingcheng Zhao MD b , Prof Neil M Ferguson DPhil c , Prof Heli Harvala PhD d , James Hope PhD e , Graham S Jackson PhD a , Prof Philip J Lowry DSc f , Prof Simon Mead PhD a , Silvia A Purro PhD a , Prof Jonathan M Schott FMedSci g h , Prof Marc L Turner PhD i , Prof David J Werring FMedSci j , Prof Henrik Zetterberg PhD g h k l m n o , Prof John Collinge FRS a
Show more
Share
Cite https://doi.org/10.1016/S0140-6736(26)00767-1 Get rights and content Summary
Seeded protein misfolding and aggregation are relevant to many neurodegenerative diseases. The archetype are prions: protein-only infectious agents that cause fatal neurodegenerative diseases including Creutzfeldt–Jakob disease (CJD). The recent recognition of iatrogenic amyloid β cerebral amyloid angiopathy (CAA) and Alzheimer's disease, caused by inadvertent seeding of amyloid β pathology following historical medical procedures, raises concerns that these conditions might also be transmitted via blood components and products, as was the case in rare instances for variant CJD. Recent epidemiological data showing the apparent transmission of haemorrhage risk between blood donors and recipients raise the possibility of blood-based CAA transmission. In this Viewpoint, we review the evidence for amyloid β transmission, provide an overview of relevant prion biology, and consider the circumstances under which bloodborne prion transmission has previously occurred. We discuss the implications for blood transfusion services, particularly in light of the UK Infected Blood Inquiry, and the key questions that need to be addressed to better quantify transfusion-related risk. Introduction
Blood transfusion is key to medical and surgical practice.1 Transfused products include blood components (eg, red cells, platelets, and clinical plasma) and plasma-derived medicinal products (eg, coagulation factors, immunoglobulins, and albumin).2Transfusion-transmitted infections are rare but potentially catastrophic,3 and even low risks of infection can undermine public confidence. In some cases, concerns that are relevant to blood transfusion can also extend to other allogeneic substances of human origin (eg, transplanted tissues, cells, and organs). In this Viewpoint, we discuss the bloodborne transmission of protein-only pathogens, or prions, given the recent recognition of iatrogenic forms of Alzheimer's disease4, 5 and iatrogenic amyloid β cerebral amyloid angiopathy (CAA).6 Section snippets
Prions and human disease
Prions are protein-only infectious agents composed of assemblies of misfolded host-encoded cellular prion protein (PrPC), which form amyloid fibrils.7 Prions propagate via a process of seeded amyloidosis, where the host PrPC is recruited by an elongating fibril that undergoes fission, producing more seeds in an autocatalytic process.7 As protein-only agents, prions are highly durable, resistant to inactivation via conventional sterilisation methods,8 and have a high binding affinity for steel Acquired amyloid β diseases: iatrogenic Alzheimer's disease and cerebral amyloid angiopathy
The amyloid β protein is traditionally associated with two diseases. The first is Alzheimer's disease, a dementia that is histopathologically characterised by parenchymal and vascular amyloid β deposition alongside aggregates of tau protein. The second is CAA, which causes intracranial haemorrhage—particularly lobar intracerebral haemorrhages—and in which amyloid β deposits are predominantly vascular.18Intracerebral haemorrhage due to CAA has a high risk of recurrence compared with Prion transmission via infected blood products
Variant CJD is a human prion disease first reported in the UK in 1996.42 Unlike other forms of CJD, there is prominent involvement of lymphoreticular tissues, raising early concerns that bloodborne prion transmission might occur via recirculating lymphocytes.43 These fears were realised, with three symptomatic cases of transfusion-associated (secondary) variant CJD following red cell transfusions; two additional people who died of other causes had variant CJD infection confirmed at autopsy in Evidence for bloodborne transmission of amyloid β
Amyloid β is detectable in blood, which plays a role in brain amyloid β clearance,51, 52 is produced by platelets,53 adheres to the surface of red blood cells,54, 55 and is a biomarker for Alzheimer's disease.56 Amyloid β has been detected in human cervical lymph nodes,57 which is an important destination for the meningeal lymphatics, glymphatic system, and other perivascular drainage pathways.58 This finding is particularly relevant, as the presence of variant CJD prions in lymphoreticular Determining amyloid β infectivity
There are no established methods for quantifying amyloid β seed titre in body fluids. Prion research has traditionally used rodent bioassays to measure infectivity, with endpoint titrations used to compare test material with serial dilutions of material with known titre. Through this method, researchers have been able to establish detection thresholds and dynamic range.69 However, unlike models of prion transmission, rodent amyloid β models do not have a clinical endpoint, and histopathological Implications for blood transfusion services
The maintenance of adequate stocks of blood components to meet highly dynamic clinical demand is essential for patient care, and anything that disrupts the balance of supply and demand has the potential to cause more harm than good. Donor numbers have fallen in the UK and internationally and their average age has increased, with blood component shortages becoming more common. The 2024 UK Infected Blood Inquiry83 investigated what has been called “the worst treatment disaster in the history of of the National Health Service (NHS).
Conclusion
The transmission of amyloid β pathology via transfused blood and blood products is a justifiable concern. We need to acknowledge that we do not have sufficient information to quantify the extent of the problem or the technologies that are needed to address key questions. Further research is essential for informing both this and future discussions and, therefore, is of strategic national and global importance. Immediate priorities should include an epidemiological replication of the Scandinavian
Declaration of interests
GB has received honoraria for teaching at Universität Bern; has received travel support from the National Institute for Health and Care Research (NIHR), UK Stroke Forum, International Cerebral Amyloid Angiopathy Association, European Stroke Organisation, and European Academy of Neurology; is an unpaid Board Member of the International Cerebral Amyloid Angiopathy Association; is funded by an MRC Clinician Scientist Fellowship; held a previous position as an NIHR Clinical Lecturer; and has
Acknowledgments
In April, 2024, the MRC Prion Unit at UCL convened a workshop to address the question of bloodborne amyloid β transmission, bringing together expert clinicians, scientists, epidemiologists, government officials, and other stakeholders to review and discuss the evidence to date and its implications. This Viewpoint is derived from presented data and roundtable discussions from this workshop. We thank all attendees for their contributions to the workshop and its discussions. The MRC Prion Unit is…
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(26)00767-1/abstract
Unforeseen decrease of full-length prion protein in macaques exposed to prion contaminated blood products
Emmanuel COMOY, Nina JAFFRE, Jérôme DELMOTTE, Jacqueline MIKOL, and Jean Philippe DESLYS Commissariat à l’Energie Atomique, DRF/IBFJ/SEPIA, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France.
Aims: The presence of prion infectivity in blood from patients affected by variant of Creutzfeldt-Jakob disease (v-CJD) questions the risk of its inter-human transmission through transfusion. We have previously described that several cynomolgus macaques experimentally exposed to prion-contaminated blood products developed c-BSE/v-CJD; however, after an exposure to low infectious doses, the vast majority of them developed an unexpected, fatal disease phenotype focused on spinal cord involvement which does not fulfill the classical diagnostic criteria of v-CJD, notably concerning the pathognomonic accumulation of abnormal prion protein. Here we aim to investigate the etiology and physiopathology of this original myelopathy.
Materials and Methods: CNS (brain and spinal cord) samples from myelopathic macaques were tested with different biochemical approaches in comparison to samples derived from either healthy animals or their counterparts exposed to different strains of prion diseases.
Results: Current conventional techniques failed to detect any accumulation of abnormal prion protein (PrPv-CJD) in the CNS of these myelopathic animals. Conversely, in their spinal cord we observed an alteration of their physiological cellular PrP pattern: PrP was not detectable under its full-length classical expression but mainly under its physiological terminal-truncated C1 fragment.
Conclusions: We here confirm the prion origin of this original syndrome, with a very specific biochemical signature linked to changes in PrP at the level of spinal cord lesions: contrary to what is classically described in prion diseases, host PrP is here altered in a form that is abnormally sensitive to degradation by cellular catabolism. This could provide the first experimental evidence of a link between loss of function of the cellular prion protein and the onset of disease. These observations open up new horizons in the field of prion diseases, which has hitherto been limited to pathologies associated with abnormal changes in cellular PrP towards highly structured conformations, with the possibility of unsuspected prion mechanisms/origins in certain neurodegenerative disorders.
Funded by: Financial support for the study was provided by the French National Research Agency (ANR).
Grant number: ANR-10-BLAN-133001 and BIOTECS2010-BloodSecur
Acknowledgement: We specially thank N. Lescoutra, A. Culeux, V. Durand, E. Correia, C. Durand and S. Jacquin for precious technical assistance
https://prion2023.org/wp-content/uploads/2023/10/Meeting-book-final-version2.pdf
The transmission of amyloid β pathology via transfused blood and blood products is a justifiable concern. We need to acknowledge that we do not have sufficient information to quantify the extent of the problem or the technologies that are needed to address key questions. Further research is essential for informing both this and future discussions and, therefore, is of strategic national and global importance. Immediate priorities should include an epidemiological replication of the Scandinavian
Declaration of interests
GB has received honoraria for teaching at Universität Bern; has received travel support from the National Institute for Health and Care Research (NIHR), UK Stroke Forum, International Cerebral Amyloid Angiopathy Association, European Stroke Organisation, and European Academy of Neurology; is an unpaid Board Member of the International Cerebral Amyloid Angiopathy Association; is funded by an MRC Clinician Scientist Fellowship; held a previous position as an NIHR Clinical Lecturer; and has
Acknowledgments
In April, 2024, the MRC Prion Unit at UCL convened a workshop to address the question of bloodborne amyloid β transmission, bringing together expert clinicians, scientists, epidemiologists, government officials, and other stakeholders to review and discuss the evidence to date and its implications. This Viewpoint is derived from presented data and roundtable discussions from this workshop. We thank all attendees for their contributions to the workshop and its discussions. The MRC Prion Unit is…
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(26)00767-1/abstract
Unforeseen decrease of full-length prion protein in macaques exposed to prion contaminated blood products
Emmanuel COMOY, Nina JAFFRE, Jérôme DELMOTTE, Jacqueline MIKOL, and Jean Philippe DESLYS Commissariat à l’Energie Atomique, DRF/IBFJ/SEPIA, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France.
Aims: The presence of prion infectivity in blood from patients affected by variant of Creutzfeldt-Jakob disease (v-CJD) questions the risk of its inter-human transmission through transfusion. We have previously described that several cynomolgus macaques experimentally exposed to prion-contaminated blood products developed c-BSE/v-CJD; however, after an exposure to low infectious doses, the vast majority of them developed an unexpected, fatal disease phenotype focused on spinal cord involvement which does not fulfill the classical diagnostic criteria of v-CJD, notably concerning the pathognomonic accumulation of abnormal prion protein. Here we aim to investigate the etiology and physiopathology of this original myelopathy.
Materials and Methods: CNS (brain and spinal cord) samples from myelopathic macaques were tested with different biochemical approaches in comparison to samples derived from either healthy animals or their counterparts exposed to different strains of prion diseases.
Results: Current conventional techniques failed to detect any accumulation of abnormal prion protein (PrPv-CJD) in the CNS of these myelopathic animals. Conversely, in their spinal cord we observed an alteration of their physiological cellular PrP pattern: PrP was not detectable under its full-length classical expression but mainly under its physiological terminal-truncated C1 fragment.
Conclusions: We here confirm the prion origin of this original syndrome, with a very specific biochemical signature linked to changes in PrP at the level of spinal cord lesions: contrary to what is classically described in prion diseases, host PrP is here altered in a form that is abnormally sensitive to degradation by cellular catabolism. This could provide the first experimental evidence of a link between loss of function of the cellular prion protein and the onset of disease. These observations open up new horizons in the field of prion diseases, which has hitherto been limited to pathologies associated with abnormal changes in cellular PrP towards highly structured conformations, with the possibility of unsuspected prion mechanisms/origins in certain neurodegenerative disorders.
Funded by: Financial support for the study was provided by the French National Research Agency (ANR).
Grant number: ANR-10-BLAN-133001 and BIOTECS2010-BloodSecur
Acknowledgement: We specially thank N. Lescoutra, A. Culeux, V. Durand, E. Correia, C. Durand and S. Jacquin for precious technical assistance
https://prion2023.org/wp-content/uploads/2023/10/Meeting-book-final-version2.pdf
https://web.archive.org/web/20250828201533/https://prion2023.org/wp-content/uploads/2023/10/Meeting-book-final-version2.pdf
https://www.researchgate.net/profile/Syed-Zahid-Shah/publication/378314391_Meeting-book-final-version_prion_2023/links/65d44dad28b7720cecdca95f/Meeting-book-final-version-prion-2023.pdf
Monday, June 26, 2023
Unexpected decrease of full-length prion protein in macaques inoculated with prion-contaminated blood products
''This concept justifies the need to revisit several neurodegenerative diseases, in particular those affecting the spinal cord, in light of our observations in primates, for which the search for abnormal PrP by conventional techniques is inadequate.''
https://bloodprp.blogspot.com/2023/06/unexpected-decrease-of-full-length.html
Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
REVIEW
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
https://familialcjdtseprion.blogspot.com/2019/02/cwd-gss-tse-prion-spinal-cord-confucius.html
Potential Risk of Variant Creutzfeldt-Jakob Disease (vCJD) From Plasma-Derived Products
In recent years, questions have been raised concerning the potential risk of variant Creutzfeldt-Jakob disease (vCJD - a rare but fatal brain infection) for recipients of plasma- derived clotting factors, including United States (US) licensed Factor Eight (pdFVIII), Factor Nine (pdFIX), and other plasma-derived products such as immune globulins and albumin. In response to these questions, FDA conducted a risk assessment. Based on the risk assessment, the US Public Health Service (PHS) believes that the risk of vCJD to patients who receive US licensed pdFVIII products is most likely to be extremely small, although we do not know the risk with certainty. vCJD risk from other plasma derived products, including Factor IX, is likely to be as small or smaller.
Additionally, the potential risk of vCJD infection from an investigational (non-US licensed) plasma-derived Factor Eleven (pdFXI) product that was made using plasma from donors in the United Kingdom (UK), and studied under IND in the US between 1989 and 2000 in a small number of subjects, has also been raised. Based on a risk assessment for this product and additional considerations, PHS believes the potential vCJD risk from this investigational pdFXI product is likely to be small.
This web page provides FDA's risk assessments for US licensed pdFVIII and the investigational pdFXI product, and risk communication materials for these products and other plasma derivatives. Included are Key Points, and Questions and Answers. Additional links are provided to FDA's current guidance documents on deferral of blood and plasma donors who may be at increased risk of vCJD, and to other sources of information regarding vCJD.
Other Sources of Information
Blood Products Advisory Committee Meeting - Summary of Recent TSEAC Meeting and Statement about FXI from the UK, on October 21, 2004 Information on vCJD: Centers for Disease Control and Prevention Information on Bovine Spongiform Encephalopathy ("Mad Cow Disease"): US Department of Agriculture Patient Organizations:
Committee of Ten Thousand Hemophilia Federation of America National Hemophilia Foundation and/or HANDI World Federation of Hemophilia Documents Regarding US Licensed pdFVIII, and Other US Licensed Plasma Derivatives Including pdFIX
Potential vCJD Risk From US Licensed Plasma-Derived Factor VIII (pdFVIII, Antihemophilic Factor) Products: Summary Information, Key Points Risk Assessment - ARCHIVEDExternal Link Disclaimer Risk Assessment Appendix - ARCHIVEDExternal Link Disclaimer Variant Creutzfeldt-Jakob Disease (vCJD) and Factor VIII (pdFVIII) Questions and Answers Variant Creutzfeldt-Jakob Disease (vCJD) and Plasma Derivatives Other than Factor VIII (pdFVIII) Questions and Answers Documents Regarding Investigational pdFXI from Donors in the UK
FDA Draft Risk Assessment:Potential Exposure to the variant Creutzfeldt-Jakob Disease Agent in United States Recipients of Factor XI Coagulation Product Manufactured in the United Kingdom - ARCHIVEDExternal Link Disclaimer Potential Variant Creutzfeldt-Jakob Disease (vCJD) Risk From Investigational Factor Eleven (pdFXI) From Donors in the United Kingdom: Summary Information, Key Points - ARCHIVEDExternal Link Disclaimer Variant Creutzfeldt-Jakob Disease (vCJD) and Factor XI (pdFXI) Questions and Answers Guidance on Donor Deferral Related to CJD and vCJD
Questions and Answers on FDA Guidance: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob (CJD) Disease and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products - ARCHIVEDExternal
Lancet Reg Health Eur. 2025 Nov 10;59:101502. doi: 10.1016/j.lanepe.2025.101502
https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/potential-risk-variant-creutzfeldt-jakob-disease-vcjd-plasma-derived-products
Estimating future variant Creutzfeldt-Jakob disease cases in the UK: a cohort-based probabilistic model
Barnaby Roberts a, James Riley a, Thomas J Evans b, Richard Knight c, Jean Manson d, Graham Medley e, Manisha Upadhyay f, Katy Sinka f, Simon Mead g,∗ Author information Article notes Copyright and License information PMCID: PMC12744720 PMID: 41466604 Summary
Background Variant Creutzfeldt–Jakob disease (vCJD) is a fatal prion disorder linked to dietary exposure to bovine spongiform encephalopathy (BSE). The epidemic peaked in the early 2000s, and no new cases have been reported in the UK since 2016. However, uncertainties remain regarding potential future cases, particularly in individuals with non-MM prion protein gene codon 129 genotypes, and possible secondary transmission via blood transfusion. We aimed to update risk estimates with recent data, informed by a probabilistic modelling approach.
Methods We developed a cohort-based probabilistic model for variant CJD incidence incorporating genotype-specific attack rates and incubation periods, accounting for competing mortality risks. Model parameters were calibrated using historical case data and life-table analyses. We explored multiple scenarios, including sensitivity analyses with alternative incubation period distributions and potential missed diagnoses. Secondary transmission risk was assessed using historical transfusion-linked cases and epidemiological data.
Findings In the base-case scenario, our model estimates a 48% probability that no further vCJD cases will occur, with a mean forecast of 2.7 additional cases. Allowing for missed past cases, estimates increased to a mean of 3.0 cases (one missed case) and 4.9 cases (four missed cases). Sensitivity analysis using a Cauchy incubation period distribution rather than a log-normal distribution increased estimates to 6.6, 9.4, and 17.9 cases, respectively. A plausible worse-case scenario, assuming very long incubation times and higher susceptibility in non-MM individuals, projected up to 65 cases of vCJD over coming decades, peaking in the 2030s. Secondary transmission risk remains negligible given transfusion safety measures, including leukodepletion since 1999.
Interpretation Our findings suggest that vCJD is unlikely to re-emerge at significant levels. However, ongoing case ascertainment and scrutiny remains critical due to uncertainties in non-MM incubation and potentially, the emergence of previously unrecognised prion strains. Continued neuropathological case investigation, maintenance of core blood safety policies, and periodic risk reassessments are essential to ensure public health preparedness and avoid unnecessary restrictions.
Funding No specific funding other than salaries of the authors. Keywords: CJD, Variant CJD, BSE, Modelling, Public health
snip…see full text;
https://pmc.ncbi.nlm.nih.gov/articles/PMC12744720/
CBC News · Posted: Jul 13, 2026 3:55 PM CDT | Last Updated: July 13
Private clinic Grifols green-lit plasma donors with disease risk, Health Canada finds
Grifols repeatedly cleared ineligible donors at risk for Creutzfeldt-Jakob disease, Health Canada report says
Deemed eligible despite disease risk: report
Grifols incorrectly deemed multiple banned donors at risk of Creutzfeld-Jakob disease as eligible, "which could compromise the safety of the blood," according to Health Canada's March 30 report, which detailed the regulator's inspection of Grifols's head office in Oakville, Ont.
Two people were barred from donating due to risks related to a rare subtype of Creutzfeld-Jakob that comes from eating beef infected with bovine spongiform encephalopathy, or "mad cow disease." That variant can be transmitted through blood.
The two were initially deferred, but those deferrals were lifted, even though both donors "continued to meet the exclusion criteria requiring an indefinite deferral," the report said.
On May 23, 2025, Grifols also lifted multiple deferrals for donors who should have been excluded for a family history of Creutzfeld-Jakob, according to Health Canada's inspection report.
While Grifols reinstated a deferral that was incorrectly lifted on one ineligible donor, no investigation was conducted, and the list of other deferred donors wasn't checked, the report says.
As a result, multiple other ineligible donors had their Creutzfeld-Jakob-related deferrals lifted on May 28, 2025, it says.
"The incomplete investigation did not adequately mitigate the risk and ensure the safety of the blood," the report says. It does not say whether any plasma was collected from these donors.
Health Canada did not respond to a request for comment by the deadline. It also did not respond to questions about an inspection of Grifols Etobicoke, Ont., location, completed June 4.
That inspection noted multiple deficiencies in donor screening, staff training and accident investigation, Health Canada's website says.
CBC requested the full inspection report but had not received a response prior to publication.
snip…see;
https://www.cbc.ca/news/canada/manitoba/grifols-donors-disease-risk-health-canada-9.7268562
https://www.drug-inspections.canada.ca/blood/initialReportCard-en.html?lang=en&insNumber=89111
Memorial for blood scandal victims permanently homed at University of Manchester Powerful reminder of the biggest treatment disaster in the history of the NHS
Katie Thompson | News Add as preferred source on Google A tribute to the victims of the UK infected blood scandal is now permanently housed at the University of Manchester.
The Infected Blood Inquiry Memorial will now reside the Old Quadrangle, on the ground floor of the Whitworth Building and is currently open to the public.
The infected blood scandal was a 1970s to 1990s UK health disaster where over 30,000 NHS patients were infected with HIV, hepatitis and Creutzfeldt-Jakob Disease (CJD) through contaminated blood products and transfusions.
In total, it is thought to be linked to around 2,900 deaths.
The Infected Blood Inquiry published its final report into the scandal in May 2024, concluding it “could largely have been avoided” and there was a “pervasive” cover-up to hide the truth. A compensation scheme was subsequently announced.
Final Report https://www.nationalhealthexecutive.com/articles/infected-blood-inquiry-worst-treatment-disaster-nhs-history-could-have-been-avoided
Since then, a government spokesperson said “the victims of the scandal have suffered unspeakable wrongs,” adding that while over £3.4 billion has been paid in compensation since then, they recognise “no amount of money will make up for the suffering endured by the infected blood community.”
“We hope that the rate of compensation paid, as well as recent consulted changes to the scheme, shows that we are committed to listening and working with the community to ensure justice, recognition and fair compensation are delivered,” the spokesperson said.
Now, a tribute to the victims of the infected blood scandal will be permanently housed at the University of Manchester, where it will remain as a place of remembrance, reflection, and learning for generations to come.
The memorial is located in the Old Quadrangle, on the ground floor of the Whitworth Building and is open to the public.
It was designed by Art Lewry, and consists of a display case filled with blood vials, each containing messages from those affected by the case. It was originally created by people attending the commemoration at the start of Inquiry hearings in 2018, but has been redesigned to display every contribution.
Christine Burney, whose husband Peter died of liver cancer after he was was given hepatitis C through contaminated blood, said: “The inquiry memorial holds deep personal significance.”
“It serves as a vital, permanent reminder of this tragedy for the medical professionals of tomorrow.”
Vice-President for Social Responsibility at the University of Manchester, Professor Nalin Thakkar, said: “It is important to remember difficult histories with honesty, compassion and respect. The Memory Bank Memorial gives powerful voice to those affected.”
Katie Thompson | News
https://thetab.com/2026/05/07/memorial-for-blood-scandal-victims-permanently-homed-at-university-of-manchester
The Inquiry Report
More on Sir Brian Langstaff's remarks and Reflections from the Publication Day can be found here.
The Government published the Response to the Inquiry Report on 14 May 2025. You can read it here.
The Government has published a dashboard of progress implementing the recommendations. You can access it here.
1. Overview and Recommendations
Summary Overview Lessons to be Learned Recommendations List of Chapters
https://www.infectedbloodinquiry.org.uk/reports/inquiry-report
nvCJD or vCJD TSE PrP, and Blood, updated information
PA03-L03 Safety profile of plasma for fractionation donated in the United Kingdom, with respect to variant Creutzfeldt-Jakob disease
S Thomas1, B Roberts2, D Domanovic3, K Kramer4, D Klochkov5, S Sivasubramaniyam6, D Miloslavich7, J Plancon8, F Rossi9, D Misztela10, L Kirkpatrick11, G Miflin12, J Birchall13, L McLintock14, R Knight15
1Joint UK Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee, 2Department of Health and Social Care, London, United Kingdom, 3European Blood Alliance, Brussels, Belgium, 4Wageningen University, Wageningen, Netherlands, 5CSL Behring, Bern, Switzerland, 6CSL Behring, Haywards Heath, United Kingdom, 7Marketing Research Bureau, Greenacres, United States, 8EPODIN, Baule, France, 9International Plasma and Fractionation Association, Amsterdam, Netherlands, 10Plasma Protein Therapeutics Association, Annapolis, United States, 1111 Northern Ireland Blood Transfusion Service, Belfast, 12NHS Blood and Transplant, London, 13Welsh Blood Service, Cardiff, 14Scottish National Blood Transfusion Service, 15UK National CJD Research & Surveillance Unit, University of Edinburgh, Edinburgh, United Kingdom
Background: Plasma-derived medicinal products (PDMPs) are life-saving and life-improving therapies, but demand is rising and the starting material is in short supply: Europe depends on importation of PDMPs manufactured with plasma from countries including the United States of America (US). Plasma from United Kingdom (UK) resident donors has not been fractionated since 1999 when this precautionary measure was introduced in response to the outbreak of variant Creutzfeldt-Jakob Disease (vCJD).
Aims: We gathered the latest evidence on the safety of UK plasma for fractionation and present it for review.
Methods: The epidemiology of vCJD over the last 23 years was reviewed, as were PDMP manufacturing processes. We reviewed recent risk assessments and regulatory policy changes in the UK and other jurisdictions, and performed a risk analysis using mathematical modelling. Blood service, industry and patient viewpoints were included, and ethical issues were considered.
Results: The vCJD outbreak was much smaller than had been feared and there have been no transfusion transmissions since 1999, when leucodepletion was introduced (allowing for an assumed eight-year incubation period more than 40M components were transfused up to 2015).
There are numerous and effective vCJD risk-reduction steps in the plasma donation and manufacturing process of PMDPs, and effective sanitisation processes in place in fractionation facilities. In February 2021, after a review by the UK Medicines and Healthcare products Regulatory Agency, the UK Government authorised the use of UK plasma to manufacture immunoglobulin for UK patients, and extended this to albumin in February 2023. Following separate reviews concluding no significant difference in the risk posed, the US, Australia, Ireland, Hong Kong and Israel also lifted their deferrals of blood donors with a history of living in the UK.
Mathematical modelling showed that the risk from each unit of donated plasma that is fractionated, using a process with a 4-log prion reduction factor (the industry minimum requirement), is over 7000 times less likely to lead to a vCJD transmission than if that unit was used for transfusion. This suggests that there would be less than one death from vCJD for every 36.4 billion units of UK plasma that are fractionated—this approximates to one possible death from vCJD transmission every 33,000 years. There is considerable uncertainty in the precision of this modelling and these numbers should be viewed with some caution but it is clear that the probability of vCJD transmission through the use of UK plasma for fractionation is extremely low.
Industry and patient groups support the review of guidelines that may enable the use of UK plasma and would bring significant immediate benefits to patients and to the resilience of the European supply chain. It is ethical to do so give the opportunity to provide significant benefits to patients currently in need of treatment.
Summary/Conclusions: UK Plasma is safe for fractionation and blood regulators and operators are strongly encouraged to review their guidelines in the context of current safety evidence and the rising demand for PDMPs in Europe.
PA03-L04 Risk of variant Creutzfeldt-Jakob disease for the Canadian blood supply
A Pozzo di Borgo1,2, M Germain3, S O'Brien4, G Delage2, C Renaud2, A Lewin2,5
1Public Health, Université de Montréal, 2Medical Affairs and Innovation, Héma-Québec, Montreal, 3Medical Affairs and Innovation, Héma-Québec, Quebec, 4Epidemiology and Surveillance, Canadian Blood Services, Ottawa, 5Medicine and Health Science, Université de Sherbrooke, Sherbrooke, Canada
Background: Despite the >20-year absence of new transfusion-associated cases of variant Creutzfeldt-Jakob disease (vCJD), transfusion-transmission remains theoretically possible due to asymptomatic carriers. Blood services have introduced donor deferrals to mitigate this risk, but this measure limits the donor base.
Aims: To estimate the risk of a donation being contaminated with vCJD (“risk of vCJD”) in Canada should current vCJD deferral criteria be lifted.
Methods: The model used Bayesian networks and a Markov chain Monte Carlo method to simulate a cohort of 10 million blood donors observed between 2023 and 2120. The model accounted for several variables that may influence the risk of vCJD, including the number of “at-risk” donors (i.e., those with an extended travel/immigration history in Western Europe), PRNP genotype at codon 129, demographics, and the type of labile blood product donated. Donors were no longer considered at risk past the incubation period, as they should be deferred by pre-donation screening. Moreover, donors were assumed to be infectious only in the late phase of the incubation period. Separate models were developed for the two blood services in Canada, that is, Héma-Québec (HQ, which operates in Québec) and Canadian Blood Services (CBS, which operates in other provinces). Two estimates of vCJD prevalence were considered: a high estimate of 1 case in 2028 individuals derived from the Appendix-II study, and a low estimate of 1 case in 588,235 individuals derived from Garske to Ghani's stochastic model. Three scenario analyses were conducted to test the sensitivity of model outputs to assumptions on vCJD prevalence (i.e., high vs. low estimate); the presence or absence of a second wave; and the proportion of deferred at-risk donors, which was reduced by 20% relative to the base case in the optimistic scenario (Table 1).
PA03-L04 - Table 1. Model scenario
Scenario vCJD prevalence in the UK Second wave % of at-risk donors Base case Low (1 in 588,235) Yes HQ = 1.90%
CBS = 3.00%
Optimistic Low (1 in 588,235) Yes HQ = 1.52%a
CBS = 2.40%a
Pessimistic i High (1 in 2028) No HQ = 1.90%
CBS = 3.00%
Pessimistic ii High (1 in 2028) Yes HQ = 1.90%
CBS = 3.00%
Results: In the base case, the simulated HQ cohort comprised 188,825 (1.9%) at-risk donors, and the CBS cohort comprised 324,313 (3.2%) such donors. Over 98 years of observation, no donors were predicted to be infectious at either blood service, and no donations would be contaminated. At HQ, the risk of vCJD was estimated at 0.0, or ≤1 in 294 million based on the upper bound of the 95% confidence interval (CI). At CBS, this risk was also estimated at 0.0, or ≤1 in 312 million based on the upper bound of the 95% CI. Similar results were obtained in the optimistic scenario, but not in pessimistic scenarios i (only for CBS) and ii. In pessimistic scenario i, at HQ, the risk of having a contaminated donation was estimated at 0.0, or ≤1 in 294 million based on the upper bound of the 95% CI. At CBS, this risk was ≤1 in 50 million based on the upper bound of the 95% CI. In pessimistic scenario ii, under the same assumption, at HQ, the risk of having a contaminated donation was estimated at ≤1 in 77 million based on the upper bound of the 95% CI. At CBS, this risk was ≤1 in 16 million based on the upper bound of the 95% CI.
Summary/Conclusions: Given that there are roughly 230,000 whole blood donations each year at Héma-Québec and 800,000 at CBS, the risk of having a vCJD-contaminated donation appears minimal in Canada (i.e., based on the 95% CI upper bound of the pessimistic scenario ii, 1 in 335 years and 1 in 20 years, respectively). These results thus support lifting current vCJD deferral criteria.
P195 Primary immunodeficiency patients exposed to UK-sourced immunoglobulin: Surveillance for asymptomatic carriage of abnormal prion protein
L Kanguru1, K Karekwaivanane1, S Lowrie1, K Ladhani2, J Cooper2, C Smith1, R Knight1
1National CJD Research & Surveillance Unit, UOE, Edinburgh, 2National Institute for Biological Standards & Control, South Mimms, United Kingdom
Background: Variant Creutzfeldt - Jakob disease (vCJD) is a very rare disease, associated with an abnormal form of prion protein. Most cases have been attributed to eating bovine spongiform encephalopathy (BSE) contaminated meat products. However, secondary transmission has occurred through blood transfusion and has been attributed, on one occasion, to treatment with a plasma product. Between 1996 and 2000, two intravenous immunoglobulin (Ig) products used to treat primary immunodeficiency diseases (PID) patients were manufactured from UK donor plasma-nine of these donors subsequently developed vCJD.
Aims: This study concerns the follow-up of patients exposed to these treatments to identify any case of vCJD, and, if found, to assess the likelihood of infection through this specific exposure.
Methods: Consenting patients had annual telephone and biennial face-to-face follow-up. Medical records were reviewed to identify any tissue and autopsy samples suitable for analysis. Blood samples were taken, anonymised and sent to the National Institute for Biological Standards and Control for storage pending possible future prion testing. PRNP-Codon 129 genotyping, histopathology, immunohistochemistry and PET blot analysis were undertaken. All cases are followed up to death or withdrawal.
Results: Of 79 cases included, none have yet shown symptoms or pathological evidence of vCJD. 58% were male, 70% born between 1960 and 1979, and 60% are still alive. The majority had a PID diagnosis of Common Variable Immunodeficiency (71%), and MM genotype (46%). The median time from first potential exposure to censor date was 20 years (range 8.9-28.2 years). Eight were known to have been treated with implicated batches (ones that included donations from pre-clinical vCJD donors), collectively contributing 155.1 person years of observation following first potential exposure. 46 cases donated 237 tissue specimens. Of these, 48 specimens from 22 cases were considered of sufficient quality (including from post-mortem). The average time from first exposure to specimen collection was 13.3 years (range 0-22.3 years). 7of the 21cases who have died underwent autopsy examination, with various causes of death, but not including vCJD: Aspiration pneumonia with disseminated carcinomatosis (1); Liver diseases (3); Alzheimer's disease/ cerebral amyloid angiopathy/progressive multifocal leucoencephalopthy (2); gastrointestinal haemorrhage of unknown cause (1).
Summary/Conclusions: We present the results of a follow-up study of patients with a potential exposure to vCJD infection via intravenous immunoglobulin products prepared from UK donor plasma, with some batches including donations from preclinical vCJD individuals. We found no evidence of transmission of vCJD, however, the incubation period from a potentially low dose exposure may be long. Uncertainties remain concerning the number of asymptomatic vCJD infections in the UK population, the risk of infection via blood components or plasma products derived from such individuals. The small number of vCJD cases, confirmed blood transmissions, and the absence of any vCJD transmission in this study is reassuring, and is evidence to support U.K. plasma being used in plasma product production. However continued surveillance for vCJD, and follow-up of these PID cases is important for public health confidence.
P282 Transmission of variant Creutzfeldt-Jakob disease through blood transfusion and plasma-derived products: a narrative review of observed and modelized risks
A Pozzo Di Borgo1, A Gaussen2, S Rochette3, S O'Brien4, M Germain2, C Renaud3, A Lewin3,5
1Public Health, Unieversité de Montréal, Montreal, 2Medical Affairs and Innovation, Héma-Québec, Québec, 3Medical Affairs and Innovation, Héma-Québec, Montreal, 4Epidemiology and surveillance, Canadian Blood Services, Ottawa, 5Medicine and health science, Université de sherbrooke, Sherbrooke, Canada
Background: Secondary transmission of variant Creutzfeldt-Jakob disease (vCJD) can occur through blood transfusion or receipt of plasma-derived products. However, published reviews on this topic are outdated, focused on a single country or product type, or did not comprehensively review how vCJD may impact the safety of the blood supply.
Aims: We reviewed existing data on observed and modelized risks of transfusion-transmission of vCJD.
Methods: We conducted a non-systematic, narrative review of relevant articles in MEDLINE. The literature was searched by three independent authors using keywords related to prion disease transmission by blood transfusion, epidemiological studies, and risk models, without restrictions on publication date. The results were supplemented with references cited by relevant articles. The references identified by each author were pooled, duplicates were removed, and the final set was selected based on consensus.
Results: To date, five patients are suspected to have acquired clinical vCJD or a vCJD infection after receiving a blood- or plasma-derived product from a donor who later developed clinical vCJD. All were transfused with non-leukodepleted red blood cells in the United Kingdom (UK) between 1996 and 1999, before the adoption of universal leukodepletion; three were methionine homozygous (MM) at codon 129 of PRNP; and two were methionine-valine heterozygotes (MV). Two UK-based, descriptive cohort studies evaluated the risk of vCJD among recipients of vCJD-implicated factor VIII concentrate (N = 787) and recipients of UK-sourced immunoglobulin (N = 75). These studies found no case of clinical vCJD over ~13 years of follow-up. Ten modeling studies were identified, including seven that reported on the risk of having a vCJD-contaminated donation, six on the risk of infection, and 6 on the risk of clinical vCJD. The risk of having a contaminated donation was generally <23 per million donations, that of infection was generally <10 per million transfusions or doses, and that of clinical vCJD was generally <2 per million transfusions or doses. Several countries have reassessed or are reassessing the need for vCJD deferral policies. Animal studies support that vCJD has preferential tropism for leukocytes and that leukoreduction is effective in reducing (but not eliminating) the risk of transmission. Prion reduction filters have been developed but are not used anywhere, possibly because of conflicting results in animal studies and the substantial costs of implementing this technology amid a waning vCJD epidemic. Despite initial concerns of a second vCJD wave driven by non-MM individuals, there has been only one autopsy-confirmed case of clinical vCJD in an MV individual. Further, the high prevalence of PrPsc-positive appendices observed in the UK (1 in 2028 individuals in the Appendix-II study) may reflect dietary exposure to the bovine spongiform encephalopathy agent rather an ongoing, active infection. According to expert consensus, should a second wave occur, no more than a few cases may arise.
Summary/Conclusions: No cases of transfusion-associated vCJD have been reported since the adoption of universal leukodepletion in the UK in 1999. Furthermore, descriptive cohort studies and modeling studies suggest the risk of having a contaminated donation is minimal. Initial concerns of a second, more significant wave have yet to materialize despite the high prevalence of PrPsc-positive appendices in the UK. Therefore, the ongoing trend to reassess or (in some countries) fully withdraw vCJD deferral criteria seems justified and may significantly expand the donor base.
P089 Removal of UK-residence deferral for variant Creutzfeldt-Jakob disease: Impact on donor sufficiency in Australia
C Seed1, V Hoad1, H McManus2, P Kiely1, C Styles1, M Law2, J Kaldor2, I Gosbell1,3
1Donor and Product Safety Unit, Australian Red Cross Lifeblood, Melbourne, 2Kirby Institute, University of New South Wales, Sydney, 3School of Medicine, Western Sydney University, Penrith, Australia
Background: Until recently, Australian Red Cross Lifeblood indefinitely deferred people with prior residency in, or extended travel to, the UK during the risk period 1980–1996 (‘UK donors’) to mitigate the potential vCJD risk to blood safety. Regulatory approval to remove the deferral was underpinned by published (McManus, Vox Sanguinis 2022) mathematical modelling that concluded its removal would not increase the risk of vCJD transfusion-transmission beyond levels considered tolerable for blood safety. The modelling predicted a substantial sufficiency benefit, estimated at approximately 17,000 donors and 58,000 donations annually. The deferral was removed on 25 July 2022.
Aims: To analyse the sufficiency impact (additional donors and donations) of removing the deferral by tracking the donation metrics of the cohort of newly eligible UK donors, in the first 6-months after the policy change.
Methods: Lifeblood's donor questionnaire retained the UK deferral screening question until a version update effective from February 12, 2023. This permitted the identification of the cohort of newly eligible donors. Their donations were tracked for the period between 25 July 2022 and 24 January 2023 (6-month study period) and compared with baseline Lifeblood donation metrics and the modelled sufficiency predictions.
Results: A total of 38,462 UK donors attended to donate 78,762 times. Of these, 32,358 donors (females = 19,456, males = 12,902) successfully donated 67,916 times during the study period, representing 8.4% of the 804,830 total Lifeblood collections, at an average collection success rate of 86.2%. Of the 67,914 total donations excluding discards and autologous (n = 276), 40,108 were fresh blood and 27,530 were plasma donations for further manufacture. The trend of weekly donations by newly eligible UK donors showed an initial peak in the first 2 weeks (4020 and 3064 for weeks 1 and 2, respectively) with a subsequent stabilisation, maintaining high donations rates with a weekly average of 2866 in the last 2 weeks of the study period.
Summary/Conclusions: Cessation of the UK residence deferral for Australian donors has resulted in sufficiency gains well exceeding modelled predictions in the continuing absence of vCJD in Australia. In the first 6-months after the deferral was removed, the 67,914 additional fresh blood and plasma donations is more than double the predicted number, and if the trend at the end of the study period continues, will result in excess of 100,000 additional donations in the first year. The model assumed that UK donors would donate at rates proportional to that of the current donor base. However, the higher than modelled number of additional donations was expected because UK donors have factors associated with a higher rate of blood donation, such as higher education status. The additional donations occurred at a time when blood supplies were low due to ongoing COVID-19 pandemic impacts, and they helped avoid a potentially more significant blood shortage. If these newly eligible donors had not donated, donations would have been 88% of the inventory target; the additional collections allowed 96% of the inventory target to be achieved. The cohort of new and returned donors appear to be highly committed and have already made a substantial contribution to supporting both plasma for fractionation inventory, as well as local red blood cell and platelet inventories.
P193 Use of fresh frozen plasma, fibrinogen concentrate and cryoprecipitate in Ireland
A Farrelly1, B Doyle1, H Moloney1, T Hervig1
1Irish Blood Transfusion Service, Dublin, Ireland
Background: Based on the risk of transfusion transmitted vCJD, Irish plasma was removed as a therapeutic component over two decades ago. Following a review process in 2018, this decision was reversed. Considering the global shortage of Plasma Derived Medicinal Products (PDMPs), Ireland is now in a position to evaluate its contribution to the European supply of plasma, and move towards the use of Fresh Frozen Plasma (FFP) sourced from the Irish donor population.
The Irish Blood Transfusion Service (IBTS) has the sole responsibility for the distribution of fibrinogen concentrate and FFP in Ireland. The IBTS imports FFP (LG Octaplas™) and fibrinogen concentrate 1g (Riastap™) to supply Irish hospitals, which cater for a population of just over 5 million. Cryoprecipitate is prepared using Irish plasma and is used for paediatric surgery only. Ireland is currently collecting approximately 38,000L of whole blood derived recovered plasma, most of which is used for in vitro diagnostics.
Aims: This study is a retrospective, ten year review of the use of FFP, fibrinogen concentrate and cryoprecipitate in Ireland. This data can provide information on product usage in a country impacted by vCJD where alternative products were sourced to meet patients’ needs.
Methods: IBTS figures for total units distributed to hospitals were collated from 2012 to 2022, for Uniplas™, Octaplas™, LG-Octaplas™, Riastap™ and Cryoprecipitate.
Results: Comparing 2012 and 2022, the FFP usage decreased from 21,122 units to 17,340 units, a 17.9% reduction. Fibrinogen concentrate (1g) usage increased from 4683 to 8955 units, a 91.2% increase. Cryoprecipitate usage decreased from 161 to 83 units, a 48.4% decrease.
Summary/Conclusions: The use of fibrinogen concentrate has widely replaced cryoprecipitate, with the exception of very limited usage in some paediatric surgery. Fibrinogen concentrate usage saw the most significant change with a 91% increase in usage since 2012. Since 2016 demand for FFP has been approximately 17,000 units per year. Demand for FFP and fibrinogen concentrate reduced in 2020 during the first year of the COVID-19 pandemic, however, demand has since increased. Demand for cryoprecipitate has decreased steadily since 2017. This product is used only in particular paediatric surgeries. The IBTS is working towards re-introducing Irish plasma for therapeutic use, both as FFP and as plasma for fractionation to make PDMPs. The figures analysed in this study will help inform the future demand for plasma in the Republic of Ireland.
P195 Primary immunodeficiency patients exposed to UK-sourced immunoglobulin: Surveillance for asymptomatic carriage of abnormal prion protein
L Kanguru1, K Karekwaivanane1, S Lowrie1, K Ladhani2, J Cooper2, C Smith1, R Knight1
1National CJD Research & Surveillance Unit, UOE, Edinburgh, 2National Institute for Biological Standards & Control, South Mimms, United Kingdom
Background: Variant Creutzfeldt - Jakob disease (vCJD) is a very rare disease, associated with an abnormal form of prion protein. Most cases have been attributed to eating bovine spongiform encephalopathy (BSE) contaminated meat products. However, secondary transmission has occurred through blood transfusion and has been attributed, on one occasion, to treatment with a plasma product. Between 1996 and 2000, two intravenous immunoglobulin (Ig) products used to treat primary immunodeficiency diseases (PID) patients were manufactured from UK donor plasma-nine of these donors subsequently developed vCJD.
Aims: This study concerns the follow-up of patients exposed to these treatments to identify any case of vCJD, and, if found, to assess the likelihood of infection through this specific exposure.
Methods: Consenting patients had annual telephone and biennial face-to-face follow-up. Medical records were reviewed to identify any tissue and autopsy samples suitable for analysis. Blood samples were taken, anonymised and sent to the National Institute for Biological Standards and Control for storage pending possible future prion testing. PRNP-Codon 129 genotyping, histopathology, immunohistochemistry and PET blot analysis were undertaken. All cases are followed up to death or withdrawal.
Results: Of 79 cases included, none have yet shown symptoms or pathological evidence of vCJD. 58% were male, 70% born between 1960 and 1979, and 60% are still alive. The majority had a PID diagnosis of Common Variable Immunodeficiency (71%), and MM genotype (46%). The median time from first potential exposure to censor date was 20 years (range 8.9-28.2 years). Eight were known to have been treated with implicated batches (ones that included donations from pre-clinical vCJD donors), collectively contributing 155.1 person years of observation following first potential exposure. 46 cases donated 237 tissue specimens. Of these, 48 specimens from 22 cases were considered of sufficient quality (including from post-mortem). The average time from first exposure to specimen collection was 13.3 years (range 0-22.3 years). 7of the 21cases who have died underwent autopsy examination, with various causes of death, but not including vCJD: Aspiration pneumonia with disseminated carcinomatosis (1); Liver diseases (3); Alzheimer's disease/ cerebral amyloid angiopathy/progressive multifocal leucoencephalopthy (2); gastrointestinal haemorrhage of unknown cause (1).
Summary/Conclusions: We present the results of a follow-up study of patients with a potential exposure to vCJD infection via intravenous immunoglobulin products prepared from UK donor plasma, with some batches including donations from preclinical vCJD individuals. We found no evidence of transmission of vCJD, however, the incubation period from a potentially low dose exposure may be long. Uncertainties remain concerning the number of asymptomatic vCJD infections in the UK population, the risk of infection via blood components or plasma products derived from such individuals. The small number of vCJD cases, confirmed blood transmissions, and the absence of any vCJD transmission in this study is reassuring, and is evidence to support U.K. plasma being used in plasma product production. However continued surveillance for vCJD, and follow-up of these PID cases is important for public health confidence.
https://onlinelibrary.wiley.com/doi/full/10.1111/vox.13433?campaign=woletoc
Thursday, June 15, 2023
nvCJD or vCJD TSE PrP, and Blood, updated information
https://bloodprp.blogspot.com/2023/06/nvcjd-or-vcjd-tse-prp-and-blood-updated.html
FDA TSE Blood Ban
the old blood ban should have been updated to include sCJD, imo, considering now that cwd to humans is going to look like sporadic CJD, and we know that CWD Blood is transmissible. sCJD is not a single strain, but many strains, and the list is growing. and GSS blood has shown to transmit to monkey. we have another new livestock prion disease outbreak CMD camel prion disease that they have no clue about yet on zoonosis. the old belief of only nvCJD ever transmitting to anything, is just wishing thinking, more of the same, putting the cart before the horse safety protocol, imo. i will never give blood no matter what FDA et al says, until there is a test to show that my blood does not have PrPtse before donating, the risk is just to high still considering my mom died from the hvCJD, they just don't know enough about all the strains of sporadic cjd, or what about (vpspr?), and now two other strange atypical variants of the infamous sporadic CJDs. imo, science still out, so i choose not to risk any one else...
Successful transmission of the chronic wasting disease (CWD) agent to white-tailed deer by intravenous blood transfusion
Najiba Mammadova a b, Eric Cassmann a b, Justin J. Greenlee a
a Virus and Prion Research Unit, National Animal Disease Center, USDA, Agricultural Research Service, 1920 Dayton Avenue, Ames, IA 50010, USA
b Oak Ridge Institute for Science and Education (ORISE), USA
Received 7 May 2020, Revised 9 October 2020, Accepted 14 October 2020, Available online 16 October 2020, Version of Record 7 December 2020.
While a previous and larger study showed similar results, we determined that only 100 mL of CWD-infected blood (~2.5 times less than previously shown in (Mathiason et al., 2010)) contained sufficient levels of prion infectivity to cause disease. The identification of blood-borne transmission of the CWD agent is important in reinforcing the risk of exposure to CWD via blood as well as the possibility of hematogenous transmission of the CWD agent through insect vector. Finally, these results further highlight the importance of developing a sensitive and reproducible blood-based test to detect pre-clinical CWD, and warrant the continued advancement and evaluation of sensitive antemortem diagnostic tests for the detection of PrPSc in blood of asymptomatic cervids early in the incubation period.
https://www.sciencedirect.com/science/article/pii/S003452882031047X
https://bloodprp.blogspot.com/2021/06/cwd-tse-prion-zoonosis-transmission-to.html
Tuesday, June 28, 2022
Subclinical infection occurs frequently following low dose exposure to prions by blood transfusion
https://bloodprp.blogspot.com/2022/06/subclinical-infection-occurs-frequently.html
Wednesday, February 3, 2021
Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients
https://itseprion.blogspot.com/2021/02/wide-distribution-of-prion-infectivity.html
WEDNESDAY, SEPTEMBER 02, 2020
Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components Guidance for Industry
https://creutzfeldt-jakob-disease.blogspot.com/2020/09/recommendations-to-reduce-possible-risk.html
blood PrP 2021 - 2025
https://bloodprp.blogspot.com/
vCJD Blood Risk 2012 - 2015
https://vcjdblood.blogspot.com/
vCJD Transfusion Risk 2007 - 2015
https://vcjdtransfusion.blogspot.com/
vCJD or what was called nvCJD
https://vcjd.blogspot.com/
TSEAC
https://tseac.blogspot.com/
SEAC
https://seac992007.blogspot.com/
Creutzfeldt Jakob Disease CJD TSE prion
https://creutzfeldt-jakob-disease.blogspot.com/
VPSPr
https://vpspr.blogspot.com/
INFECTED BLOOD INQUIRY THE REPORT MAY 20, 2024
https://www.infectedbloodinquiry.org.uk/reports/inquiry-report
FOR anyone interested, you can see my old files from the early nvCJD blood scandal days, and the BSE Inquiry...terry
BSE Inquiry
https://www.infectedbloodinquiry.org.uk/sites/default/files/Volume-7.pdf
BSE Inquiry
Sunday, May 18, 2008 BSE, CJD, and Baby foods (the great debate 1999 to 2005)
http://bseinquiry.blogspot.com/2008/05/bse-cjd-and-baby-foods-great-debate.html
TUESDAY, AUGUST 1, 2017
BSE INQUIRY DFA 17 Medicines and medical devices
http://bseinquiry.blogspot.com/2017/08/bse-inquiry-dfa-17-medicines-and.html
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html
http://bseinquiry.blogspot.com/2018/06/vaccines-tse-prion-risk-factors.html
MONDAY, MAY 19, 2008
SPORADIC CJD IN FARMERS, FARMERS WIVES, FROM FARMS WITH BSE HERD AND ABATTOIRS
http://bseinquiry.blogspot.com/2008/05/sporadic-cjd-in-farmers-farmers-wives.html
THURSDAY, JULY 22, 2010
BSE INQUIRY DFA 18 COSMETICS
http://bseinquiry.blogspot.com/2010/07/bse-inquiry-dfa-18-cosmetics.html
Sunday, May 18, 2008
BSE Inquiry DRAFT FACTUAL ACCOUNT DFA
BSE Inquiry DRAFT FACTUAL ACCOUNTS DFA's
http://bseinquiry.blogspot.com/2008/05/bse-inquiry-draft-factual-account-dfa.html
DFA 15 Monitoring and Enforcement of the SBO Specified Bovine Offal Regulations
http://bseinquiry.blogspot.com/2017/08/dfa-15-monitoring-and-enforcement-of.html
SATURDAY, AUGUST 26, 2017
DFA 14 Consideration of the Risk from Mechanically Recovered Meat (MRM) in 1989-1990
https://bseinquiry.blogspot.com/2017/08/dfa-14-consideration-of-risk-from.html
BSE INQUIRY DFA 16 MID 1995 TO THE FINAL DAYS
https://bseinquiry.blogspot.com/2017/08/bse-inquiry-dfa-16-mid-1995-to-final.html
BSE INQUIRY DFA
http://bseinquiry.blogspot.com/2012/04/wendy-grant-who-has-died-aged-89-was.html
nvCJD blood transfusion risks
https://vcjdblood.blogspot.com/
https://vcjdtransfusion.blogspot.com/
SEAC
https://seac992007.blogspot.com/
Singeltary Submission SEAC 2007
SEAC SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Minutes of the 99th meeting held on 14th December 2007 Singeltary Submission
This was 22 years to the day Mom died from the Heidenhain Variant of Creutzfeldt Jakob Disease i.e. hvCJD, when i made this submission to SEAC and this was their reply to my questions of concern about cjd in the USA, my how things have changed...terry
SEAC SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Minutes of the 99th meeting held on 14th December 2007
ITEM 8 – PUBLIC QUESTION AND ANSWER SESSION 40. The Chair explained that the purpose of the question and answer session was to give members of the public an opportunity to ask questions related to the work of SEAC. Mr Terry Singeltary (Texas, USA) had submitted a question prior to the meeting, asking: “With the Nor-98 now documented in five different states so far in the USA in 2007, and with the two atypical BSE H-base cases in Texas and Alabama, with both scrapie and chronic wasting disease (CWD) running rampant in the USA, is there any concern from SEAC with the rise of sporadic CJD in the USA from ''unknown phenotype'', and what concerns if any, in relations to blood donations, surgery, optical, and dental treatment, do you have with these unknown atypical phenotypes in both humans and animals in the USA? Does it concern SEAC, or is it of no concern to SEAC? Should it concern USA animal and human health officials?”
41. A member considered that this question appeared to be primarily related to possible links between animal and human TSEs in the USA. There is no evidence that sCJD is increasing in the USA and no evidence of any direct link between TSEs and CJD in the USA. Current evidence does not suggest that CWD is a significant risk to human health. There are unpublished data from a case of human TSE in the USA that are suggestive of an apparently novel form of prion disease with distinct molecular characteristics. However, it is unclear whether the case had been further characterised, if it could be linked to animal TSEs or if other similar cases had been found in the USA or elsewhere. In relation to the possible public health implications of atypical scrapie, H-type BSE and CWD, research was being conducted to investigate possible links and surveillance was in place to detect any changes in human TSEs. Although possible links between these diseases and human TSEs are of concern and require research, there is no evidence to suggest immediate public health action is warranted. The possible human health risks from classical scrapie had been discussed earlier in the meeting. Members noted that there are effective channels of discussion and collaboration on research between USA and European groups. Members agreed it is important to keep a watching brief on new developments on TSEs.
http://web.archive.org/web/20091010132933/http://www.seac.gov.uk/minutes/99.pdf
BLOODPRP UPDATED INFORMATION
https://bloodprp.blogspot.com/2024/03/transmissible-spongiform-encephalopathy.html
https://vcjd.blogspot.com/
Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk
Authors Lauren A. Crowder, Lawrence B. Schonberger, Roger Y. Dodd, Whitney R. Steele First published: 25 April 2017Full publication history DOI: 10.1111/trf.14145 View/save citation Cited by (CrossRef): 0 articles Check for updates Citation tools Funding Information
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
This work has been funded by Grant 2 U01 CK000360-03 from the US Centers for Disease Control and Prevention.
Abstract
BACKGROUND
Transfusion transmission of human prion diseases has been observed for variant Creutzfeldt-Jakob disease (vCJD), but not for the classic forms of prion disease (CJD: sporadic, genetic, and iatrogenic). Although the presence of prions or misfolded prion proteins in blood has been documented in some patients with the most common form of CJD, sporadic CJD, no transfusion-transmitted cases of CJD have been recognized. Since 1995, the American Red Cross has conducted a lookback study of the recipients of blood products from donors who develop CJD to assess the risk of blood-borne CJD transmission in the United States.
STUDY DESIGN AND METHODS
Blood donors subsequently diagnosed with confirmed or probable CJD were enrolled and the consignees were asked to identify the recipients of their blood products. These donors' transfusion recipients are traced annually with the National Death Index to see if they subsequently die of CJD.
RESULTS
To date, 65 CJD donors have been enrolled along with 826 of their blood recipients. These recipients have contributed 3934 person-years of follow-up and no transfusion-transmitted cases of CJD have been recognized.
CONCLUSION
From this study, as well as other epidemiologic studies, there is no evidence of CJD transfusion transmission; this risk remains theoretical.
http://onlinelibrary.wiley.com/doi/10.1111/trf.14145/abstract?campaign=wolearlyview
SUNDAY, MARCH 09, 2014
A Creutzfeldt-Jakob Disease (CJD) Lookback Study: Assessing the Risk of Blood Borne Transmission of Classic Forms of Creutzfeldt-Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/2014/03/a-creutzfeldt-jakob-disease-cjd.html
SATURDAY, DECEMBER 08, 2007
Transfusion Transmission of Human Prion Diseases
http://vcjdblood.blogspot.com/2007/12/transfusion-transmission-of-human-prion.html
Tuesday, November 29, 2016
Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: new insights into the molecular underpinnings of prion infectivity
http://transmissiblespongiformencephalopathy.blogspot.com/2016/11/transmissibility-of-gerstmannstraussler.html
2017, please note concern, a few recent studies...kindest regards, terry
In summary, PrPsc was detectable at high levels in organs and tissues of the LRS only in BSE/vCJD infected animals (0.1% to 10% of the amounts found in the brains of the same animals). We interpreted these results as the BSE prion being highly lymphotropic in primates. These findings correlated indeed with the tonsils, spleens and appendices of vCJD patients being found positive for PrPsc18,19,20). We therefore proposed that LRS tissues be considered ‘high-risk’ in vCJD patients only.
However, lower amounts of PrPsc were detected in adrenals, muscles and intestinal tissue of macaques infected with BSE/vCJD as well as sCJD and iCJD, associated with peripheral nerves. Levels were less than 10,000 times lower than brain PrPres levels (<0.001%).
https://www.researchgate.net/profile/Syed-Zahid-Shah/publication/378314391_Meeting-book-final-version_prion_2023/links/65d44dad28b7720cecdca95f/Meeting-book-final-version-prion-2023.pdf
Monday, June 26, 2023
Unexpected decrease of full-length prion protein in macaques inoculated with prion-contaminated blood products
''This concept justifies the need to revisit several neurodegenerative diseases, in particular those affecting the spinal cord, in light of our observations in primates, for which the search for abnormal PrP by conventional techniques is inadequate.''
https://bloodprp.blogspot.com/2023/06/unexpected-decrease-of-full-length.html
Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
REVIEW
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
https://familialcjdtseprion.blogspot.com/2019/02/cwd-gss-tse-prion-spinal-cord-confucius.html
Potential Risk of Variant Creutzfeldt-Jakob Disease (vCJD) From Plasma-Derived Products
In recent years, questions have been raised concerning the potential risk of variant Creutzfeldt-Jakob disease (vCJD - a rare but fatal brain infection) for recipients of plasma- derived clotting factors, including United States (US) licensed Factor Eight (pdFVIII), Factor Nine (pdFIX), and other plasma-derived products such as immune globulins and albumin. In response to these questions, FDA conducted a risk assessment. Based on the risk assessment, the US Public Health Service (PHS) believes that the risk of vCJD to patients who receive US licensed pdFVIII products is most likely to be extremely small, although we do not know the risk with certainty. vCJD risk from other plasma derived products, including Factor IX, is likely to be as small or smaller.
Additionally, the potential risk of vCJD infection from an investigational (non-US licensed) plasma-derived Factor Eleven (pdFXI) product that was made using plasma from donors in the United Kingdom (UK), and studied under IND in the US between 1989 and 2000 in a small number of subjects, has also been raised. Based on a risk assessment for this product and additional considerations, PHS believes the potential vCJD risk from this investigational pdFXI product is likely to be small.
This web page provides FDA's risk assessments for US licensed pdFVIII and the investigational pdFXI product, and risk communication materials for these products and other plasma derivatives. Included are Key Points, and Questions and Answers. Additional links are provided to FDA's current guidance documents on deferral of blood and plasma donors who may be at increased risk of vCJD, and to other sources of information regarding vCJD.
Other Sources of Information
Blood Products Advisory Committee Meeting - Summary of Recent TSEAC Meeting and Statement about FXI from the UK, on October 21, 2004 Information on vCJD: Centers for Disease Control and Prevention Information on Bovine Spongiform Encephalopathy ("Mad Cow Disease"): US Department of Agriculture Patient Organizations:
Committee of Ten Thousand Hemophilia Federation of America National Hemophilia Foundation and/or HANDI World Federation of Hemophilia Documents Regarding US Licensed pdFVIII, and Other US Licensed Plasma Derivatives Including pdFIX
Potential vCJD Risk From US Licensed Plasma-Derived Factor VIII (pdFVIII, Antihemophilic Factor) Products: Summary Information, Key Points Risk Assessment - ARCHIVEDExternal Link Disclaimer Risk Assessment Appendix - ARCHIVEDExternal Link Disclaimer Variant Creutzfeldt-Jakob Disease (vCJD) and Factor VIII (pdFVIII) Questions and Answers Variant Creutzfeldt-Jakob Disease (vCJD) and Plasma Derivatives Other than Factor VIII (pdFVIII) Questions and Answers Documents Regarding Investigational pdFXI from Donors in the UK
FDA Draft Risk Assessment:Potential Exposure to the variant Creutzfeldt-Jakob Disease Agent in United States Recipients of Factor XI Coagulation Product Manufactured in the United Kingdom - ARCHIVEDExternal Link Disclaimer Potential Variant Creutzfeldt-Jakob Disease (vCJD) Risk From Investigational Factor Eleven (pdFXI) From Donors in the United Kingdom: Summary Information, Key Points - ARCHIVEDExternal Link Disclaimer Variant Creutzfeldt-Jakob Disease (vCJD) and Factor XI (pdFXI) Questions and Answers Guidance on Donor Deferral Related to CJD and vCJD
Questions and Answers on FDA Guidance: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob (CJD) Disease and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products - ARCHIVEDExternal
Lancet Reg Health Eur. 2025 Nov 10;59:101502. doi: 10.1016/j.lanepe.2025.101502
https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/potential-risk-variant-creutzfeldt-jakob-disease-vcjd-plasma-derived-products
Estimating future variant Creutzfeldt-Jakob disease cases in the UK: a cohort-based probabilistic model
Barnaby Roberts a, James Riley a, Thomas J Evans b, Richard Knight c, Jean Manson d, Graham Medley e, Manisha Upadhyay f, Katy Sinka f, Simon Mead g,∗ Author information Article notes Copyright and License information PMCID: PMC12744720 PMID: 41466604 Summary
Background Variant Creutzfeldt–Jakob disease (vCJD) is a fatal prion disorder linked to dietary exposure to bovine spongiform encephalopathy (BSE). The epidemic peaked in the early 2000s, and no new cases have been reported in the UK since 2016. However, uncertainties remain regarding potential future cases, particularly in individuals with non-MM prion protein gene codon 129 genotypes, and possible secondary transmission via blood transfusion. We aimed to update risk estimates with recent data, informed by a probabilistic modelling approach.
Methods We developed a cohort-based probabilistic model for variant CJD incidence incorporating genotype-specific attack rates and incubation periods, accounting for competing mortality risks. Model parameters were calibrated using historical case data and life-table analyses. We explored multiple scenarios, including sensitivity analyses with alternative incubation period distributions and potential missed diagnoses. Secondary transmission risk was assessed using historical transfusion-linked cases and epidemiological data.
Findings In the base-case scenario, our model estimates a 48% probability that no further vCJD cases will occur, with a mean forecast of 2.7 additional cases. Allowing for missed past cases, estimates increased to a mean of 3.0 cases (one missed case) and 4.9 cases (four missed cases). Sensitivity analysis using a Cauchy incubation period distribution rather than a log-normal distribution increased estimates to 6.6, 9.4, and 17.9 cases, respectively. A plausible worse-case scenario, assuming very long incubation times and higher susceptibility in non-MM individuals, projected up to 65 cases of vCJD over coming decades, peaking in the 2030s. Secondary transmission risk remains negligible given transfusion safety measures, including leukodepletion since 1999.
Interpretation Our findings suggest that vCJD is unlikely to re-emerge at significant levels. However, ongoing case ascertainment and scrutiny remains critical due to uncertainties in non-MM incubation and potentially, the emergence of previously unrecognised prion strains. Continued neuropathological case investigation, maintenance of core blood safety policies, and periodic risk reassessments are essential to ensure public health preparedness and avoid unnecessary restrictions.
Funding No specific funding other than salaries of the authors. Keywords: CJD, Variant CJD, BSE, Modelling, Public health
snip…see full text;
https://pmc.ncbi.nlm.nih.gov/articles/PMC12744720/
CBC News · Posted: Jul 13, 2026 3:55 PM CDT | Last Updated: July 13
Private clinic Grifols green-lit plasma donors with disease risk, Health Canada finds
Grifols repeatedly cleared ineligible donors at risk for Creutzfeldt-Jakob disease, Health Canada report says
Deemed eligible despite disease risk: report
Grifols incorrectly deemed multiple banned donors at risk of Creutzfeld-Jakob disease as eligible, "which could compromise the safety of the blood," according to Health Canada's March 30 report, which detailed the regulator's inspection of Grifols's head office in Oakville, Ont.
Two people were barred from donating due to risks related to a rare subtype of Creutzfeld-Jakob that comes from eating beef infected with bovine spongiform encephalopathy, or "mad cow disease." That variant can be transmitted through blood.
The two were initially deferred, but those deferrals were lifted, even though both donors "continued to meet the exclusion criteria requiring an indefinite deferral," the report said.
On May 23, 2025, Grifols also lifted multiple deferrals for donors who should have been excluded for a family history of Creutzfeld-Jakob, according to Health Canada's inspection report.
While Grifols reinstated a deferral that was incorrectly lifted on one ineligible donor, no investigation was conducted, and the list of other deferred donors wasn't checked, the report says.
As a result, multiple other ineligible donors had their Creutzfeld-Jakob-related deferrals lifted on May 28, 2025, it says.
"The incomplete investigation did not adequately mitigate the risk and ensure the safety of the blood," the report says. It does not say whether any plasma was collected from these donors.
Health Canada did not respond to a request for comment by the deadline. It also did not respond to questions about an inspection of Grifols Etobicoke, Ont., location, completed June 4.
That inspection noted multiple deficiencies in donor screening, staff training and accident investigation, Health Canada's website says.
CBC requested the full inspection report but had not received a response prior to publication.
snip…see;
https://www.cbc.ca/news/canada/manitoba/grifols-donors-disease-risk-health-canada-9.7268562
https://www.drug-inspections.canada.ca/blood/initialReportCard-en.html?lang=en&insNumber=89111
Memorial for blood scandal victims permanently homed at University of Manchester Powerful reminder of the biggest treatment disaster in the history of the NHS
Katie Thompson | News Add as preferred source on Google A tribute to the victims of the UK infected blood scandal is now permanently housed at the University of Manchester.
The Infected Blood Inquiry Memorial will now reside the Old Quadrangle, on the ground floor of the Whitworth Building and is currently open to the public.
The infected blood scandal was a 1970s to 1990s UK health disaster where over 30,000 NHS patients were infected with HIV, hepatitis and Creutzfeldt-Jakob Disease (CJD) through contaminated blood products and transfusions.
In total, it is thought to be linked to around 2,900 deaths.
The Infected Blood Inquiry published its final report into the scandal in May 2024, concluding it “could largely have been avoided” and there was a “pervasive” cover-up to hide the truth. A compensation scheme was subsequently announced.
Final Report https://www.nationalhealthexecutive.com/articles/infected-blood-inquiry-worst-treatment-disaster-nhs-history-could-have-been-avoided
Since then, a government spokesperson said “the victims of the scandal have suffered unspeakable wrongs,” adding that while over £3.4 billion has been paid in compensation since then, they recognise “no amount of money will make up for the suffering endured by the infected blood community.”
“We hope that the rate of compensation paid, as well as recent consulted changes to the scheme, shows that we are committed to listening and working with the community to ensure justice, recognition and fair compensation are delivered,” the spokesperson said.
Now, a tribute to the victims of the infected blood scandal will be permanently housed at the University of Manchester, where it will remain as a place of remembrance, reflection, and learning for generations to come.
The memorial is located in the Old Quadrangle, on the ground floor of the Whitworth Building and is open to the public.
It was designed by Art Lewry, and consists of a display case filled with blood vials, each containing messages from those affected by the case. It was originally created by people attending the commemoration at the start of Inquiry hearings in 2018, but has been redesigned to display every contribution.
Christine Burney, whose husband Peter died of liver cancer after he was was given hepatitis C through contaminated blood, said: “The inquiry memorial holds deep personal significance.”
“It serves as a vital, permanent reminder of this tragedy for the medical professionals of tomorrow.”
Vice-President for Social Responsibility at the University of Manchester, Professor Nalin Thakkar, said: “It is important to remember difficult histories with honesty, compassion and respect. The Memory Bank Memorial gives powerful voice to those affected.”
Katie Thompson | News
https://thetab.com/2026/05/07/memorial-for-blood-scandal-victims-permanently-homed-at-university-of-manchester
The Inquiry Report
More on Sir Brian Langstaff's remarks and Reflections from the Publication Day can be found here.
The Government published the Response to the Inquiry Report on 14 May 2025. You can read it here.
The Government has published a dashboard of progress implementing the recommendations. You can access it here.
1. Overview and Recommendations
Summary Overview Lessons to be Learned Recommendations List of Chapters
https://www.infectedbloodinquiry.org.uk/reports/inquiry-report
nvCJD or vCJD TSE PrP, and Blood, updated information
PA03-L03 Safety profile of plasma for fractionation donated in the United Kingdom, with respect to variant Creutzfeldt-Jakob disease
S Thomas1, B Roberts2, D Domanovic3, K Kramer4, D Klochkov5, S Sivasubramaniyam6, D Miloslavich7, J Plancon8, F Rossi9, D Misztela10, L Kirkpatrick11, G Miflin12, J Birchall13, L McLintock14, R Knight15
1Joint UK Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee, 2Department of Health and Social Care, London, United Kingdom, 3European Blood Alliance, Brussels, Belgium, 4Wageningen University, Wageningen, Netherlands, 5CSL Behring, Bern, Switzerland, 6CSL Behring, Haywards Heath, United Kingdom, 7Marketing Research Bureau, Greenacres, United States, 8EPODIN, Baule, France, 9International Plasma and Fractionation Association, Amsterdam, Netherlands, 10Plasma Protein Therapeutics Association, Annapolis, United States, 1111 Northern Ireland Blood Transfusion Service, Belfast, 12NHS Blood and Transplant, London, 13Welsh Blood Service, Cardiff, 14Scottish National Blood Transfusion Service, 15UK National CJD Research & Surveillance Unit, University of Edinburgh, Edinburgh, United Kingdom
Background: Plasma-derived medicinal products (PDMPs) are life-saving and life-improving therapies, but demand is rising and the starting material is in short supply: Europe depends on importation of PDMPs manufactured with plasma from countries including the United States of America (US). Plasma from United Kingdom (UK) resident donors has not been fractionated since 1999 when this precautionary measure was introduced in response to the outbreak of variant Creutzfeldt-Jakob Disease (vCJD).
Aims: We gathered the latest evidence on the safety of UK plasma for fractionation and present it for review.
Methods: The epidemiology of vCJD over the last 23 years was reviewed, as were PDMP manufacturing processes. We reviewed recent risk assessments and regulatory policy changes in the UK and other jurisdictions, and performed a risk analysis using mathematical modelling. Blood service, industry and patient viewpoints were included, and ethical issues were considered.
Results: The vCJD outbreak was much smaller than had been feared and there have been no transfusion transmissions since 1999, when leucodepletion was introduced (allowing for an assumed eight-year incubation period more than 40M components were transfused up to 2015).
There are numerous and effective vCJD risk-reduction steps in the plasma donation and manufacturing process of PMDPs, and effective sanitisation processes in place in fractionation facilities. In February 2021, after a review by the UK Medicines and Healthcare products Regulatory Agency, the UK Government authorised the use of UK plasma to manufacture immunoglobulin for UK patients, and extended this to albumin in February 2023. Following separate reviews concluding no significant difference in the risk posed, the US, Australia, Ireland, Hong Kong and Israel also lifted their deferrals of blood donors with a history of living in the UK.
Mathematical modelling showed that the risk from each unit of donated plasma that is fractionated, using a process with a 4-log prion reduction factor (the industry minimum requirement), is over 7000 times less likely to lead to a vCJD transmission than if that unit was used for transfusion. This suggests that there would be less than one death from vCJD for every 36.4 billion units of UK plasma that are fractionated—this approximates to one possible death from vCJD transmission every 33,000 years. There is considerable uncertainty in the precision of this modelling and these numbers should be viewed with some caution but it is clear that the probability of vCJD transmission through the use of UK plasma for fractionation is extremely low.
Industry and patient groups support the review of guidelines that may enable the use of UK plasma and would bring significant immediate benefits to patients and to the resilience of the European supply chain. It is ethical to do so give the opportunity to provide significant benefits to patients currently in need of treatment.
Summary/Conclusions: UK Plasma is safe for fractionation and blood regulators and operators are strongly encouraged to review their guidelines in the context of current safety evidence and the rising demand for PDMPs in Europe.
PA03-L04 Risk of variant Creutzfeldt-Jakob disease for the Canadian blood supply
A Pozzo di Borgo1,2, M Germain3, S O'Brien4, G Delage2, C Renaud2, A Lewin2,5
1Public Health, Université de Montréal, 2Medical Affairs and Innovation, Héma-Québec, Montreal, 3Medical Affairs and Innovation, Héma-Québec, Quebec, 4Epidemiology and Surveillance, Canadian Blood Services, Ottawa, 5Medicine and Health Science, Université de Sherbrooke, Sherbrooke, Canada
Background: Despite the >20-year absence of new transfusion-associated cases of variant Creutzfeldt-Jakob disease (vCJD), transfusion-transmission remains theoretically possible due to asymptomatic carriers. Blood services have introduced donor deferrals to mitigate this risk, but this measure limits the donor base.
Aims: To estimate the risk of a donation being contaminated with vCJD (“risk of vCJD”) in Canada should current vCJD deferral criteria be lifted.
Methods: The model used Bayesian networks and a Markov chain Monte Carlo method to simulate a cohort of 10 million blood donors observed between 2023 and 2120. The model accounted for several variables that may influence the risk of vCJD, including the number of “at-risk” donors (i.e., those with an extended travel/immigration history in Western Europe), PRNP genotype at codon 129, demographics, and the type of labile blood product donated. Donors were no longer considered at risk past the incubation period, as they should be deferred by pre-donation screening. Moreover, donors were assumed to be infectious only in the late phase of the incubation period. Separate models were developed for the two blood services in Canada, that is, Héma-Québec (HQ, which operates in Québec) and Canadian Blood Services (CBS, which operates in other provinces). Two estimates of vCJD prevalence were considered: a high estimate of 1 case in 2028 individuals derived from the Appendix-II study, and a low estimate of 1 case in 588,235 individuals derived from Garske to Ghani's stochastic model. Three scenario analyses were conducted to test the sensitivity of model outputs to assumptions on vCJD prevalence (i.e., high vs. low estimate); the presence or absence of a second wave; and the proportion of deferred at-risk donors, which was reduced by 20% relative to the base case in the optimistic scenario (Table 1).
PA03-L04 - Table 1. Model scenario
Scenario vCJD prevalence in the UK Second wave % of at-risk donors Base case Low (1 in 588,235) Yes HQ = 1.90%
CBS = 3.00%
Optimistic Low (1 in 588,235) Yes HQ = 1.52%a
CBS = 2.40%a
Pessimistic i High (1 in 2028) No HQ = 1.90%
CBS = 3.00%
Pessimistic ii High (1 in 2028) Yes HQ = 1.90%
CBS = 3.00%
Results: In the base case, the simulated HQ cohort comprised 188,825 (1.9%) at-risk donors, and the CBS cohort comprised 324,313 (3.2%) such donors. Over 98 years of observation, no donors were predicted to be infectious at either blood service, and no donations would be contaminated. At HQ, the risk of vCJD was estimated at 0.0, or ≤1 in 294 million based on the upper bound of the 95% confidence interval (CI). At CBS, this risk was also estimated at 0.0, or ≤1 in 312 million based on the upper bound of the 95% CI. Similar results were obtained in the optimistic scenario, but not in pessimistic scenarios i (only for CBS) and ii. In pessimistic scenario i, at HQ, the risk of having a contaminated donation was estimated at 0.0, or ≤1 in 294 million based on the upper bound of the 95% CI. At CBS, this risk was ≤1 in 50 million based on the upper bound of the 95% CI. In pessimistic scenario ii, under the same assumption, at HQ, the risk of having a contaminated donation was estimated at ≤1 in 77 million based on the upper bound of the 95% CI. At CBS, this risk was ≤1 in 16 million based on the upper bound of the 95% CI.
Summary/Conclusions: Given that there are roughly 230,000 whole blood donations each year at Héma-Québec and 800,000 at CBS, the risk of having a vCJD-contaminated donation appears minimal in Canada (i.e., based on the 95% CI upper bound of the pessimistic scenario ii, 1 in 335 years and 1 in 20 years, respectively). These results thus support lifting current vCJD deferral criteria.
P195 Primary immunodeficiency patients exposed to UK-sourced immunoglobulin: Surveillance for asymptomatic carriage of abnormal prion protein
L Kanguru1, K Karekwaivanane1, S Lowrie1, K Ladhani2, J Cooper2, C Smith1, R Knight1
1National CJD Research & Surveillance Unit, UOE, Edinburgh, 2National Institute for Biological Standards & Control, South Mimms, United Kingdom
Background: Variant Creutzfeldt - Jakob disease (vCJD) is a very rare disease, associated with an abnormal form of prion protein. Most cases have been attributed to eating bovine spongiform encephalopathy (BSE) contaminated meat products. However, secondary transmission has occurred through blood transfusion and has been attributed, on one occasion, to treatment with a plasma product. Between 1996 and 2000, two intravenous immunoglobulin (Ig) products used to treat primary immunodeficiency diseases (PID) patients were manufactured from UK donor plasma-nine of these donors subsequently developed vCJD.
Aims: This study concerns the follow-up of patients exposed to these treatments to identify any case of vCJD, and, if found, to assess the likelihood of infection through this specific exposure.
Methods: Consenting patients had annual telephone and biennial face-to-face follow-up. Medical records were reviewed to identify any tissue and autopsy samples suitable for analysis. Blood samples were taken, anonymised and sent to the National Institute for Biological Standards and Control for storage pending possible future prion testing. PRNP-Codon 129 genotyping, histopathology, immunohistochemistry and PET blot analysis were undertaken. All cases are followed up to death or withdrawal.
Results: Of 79 cases included, none have yet shown symptoms or pathological evidence of vCJD. 58% were male, 70% born between 1960 and 1979, and 60% are still alive. The majority had a PID diagnosis of Common Variable Immunodeficiency (71%), and MM genotype (46%). The median time from first potential exposure to censor date was 20 years (range 8.9-28.2 years). Eight were known to have been treated with implicated batches (ones that included donations from pre-clinical vCJD donors), collectively contributing 155.1 person years of observation following first potential exposure. 46 cases donated 237 tissue specimens. Of these, 48 specimens from 22 cases were considered of sufficient quality (including from post-mortem). The average time from first exposure to specimen collection was 13.3 years (range 0-22.3 years). 7of the 21cases who have died underwent autopsy examination, with various causes of death, but not including vCJD: Aspiration pneumonia with disseminated carcinomatosis (1); Liver diseases (3); Alzheimer's disease/ cerebral amyloid angiopathy/progressive multifocal leucoencephalopthy (2); gastrointestinal haemorrhage of unknown cause (1).
Summary/Conclusions: We present the results of a follow-up study of patients with a potential exposure to vCJD infection via intravenous immunoglobulin products prepared from UK donor plasma, with some batches including donations from preclinical vCJD individuals. We found no evidence of transmission of vCJD, however, the incubation period from a potentially low dose exposure may be long. Uncertainties remain concerning the number of asymptomatic vCJD infections in the UK population, the risk of infection via blood components or plasma products derived from such individuals. The small number of vCJD cases, confirmed blood transmissions, and the absence of any vCJD transmission in this study is reassuring, and is evidence to support U.K. plasma being used in plasma product production. However continued surveillance for vCJD, and follow-up of these PID cases is important for public health confidence.
P282 Transmission of variant Creutzfeldt-Jakob disease through blood transfusion and plasma-derived products: a narrative review of observed and modelized risks
A Pozzo Di Borgo1, A Gaussen2, S Rochette3, S O'Brien4, M Germain2, C Renaud3, A Lewin3,5
1Public Health, Unieversité de Montréal, Montreal, 2Medical Affairs and Innovation, Héma-Québec, Québec, 3Medical Affairs and Innovation, Héma-Québec, Montreal, 4Epidemiology and surveillance, Canadian Blood Services, Ottawa, 5Medicine and health science, Université de sherbrooke, Sherbrooke, Canada
Background: Secondary transmission of variant Creutzfeldt-Jakob disease (vCJD) can occur through blood transfusion or receipt of plasma-derived products. However, published reviews on this topic are outdated, focused on a single country or product type, or did not comprehensively review how vCJD may impact the safety of the blood supply.
Aims: We reviewed existing data on observed and modelized risks of transfusion-transmission of vCJD.
Methods: We conducted a non-systematic, narrative review of relevant articles in MEDLINE. The literature was searched by three independent authors using keywords related to prion disease transmission by blood transfusion, epidemiological studies, and risk models, without restrictions on publication date. The results were supplemented with references cited by relevant articles. The references identified by each author were pooled, duplicates were removed, and the final set was selected based on consensus.
Results: To date, five patients are suspected to have acquired clinical vCJD or a vCJD infection after receiving a blood- or plasma-derived product from a donor who later developed clinical vCJD. All were transfused with non-leukodepleted red blood cells in the United Kingdom (UK) between 1996 and 1999, before the adoption of universal leukodepletion; three were methionine homozygous (MM) at codon 129 of PRNP; and two were methionine-valine heterozygotes (MV). Two UK-based, descriptive cohort studies evaluated the risk of vCJD among recipients of vCJD-implicated factor VIII concentrate (N = 787) and recipients of UK-sourced immunoglobulin (N = 75). These studies found no case of clinical vCJD over ~13 years of follow-up. Ten modeling studies were identified, including seven that reported on the risk of having a vCJD-contaminated donation, six on the risk of infection, and 6 on the risk of clinical vCJD. The risk of having a contaminated donation was generally <23 per million donations, that of infection was generally <10 per million transfusions or doses, and that of clinical vCJD was generally <2 per million transfusions or doses. Several countries have reassessed or are reassessing the need for vCJD deferral policies. Animal studies support that vCJD has preferential tropism for leukocytes and that leukoreduction is effective in reducing (but not eliminating) the risk of transmission. Prion reduction filters have been developed but are not used anywhere, possibly because of conflicting results in animal studies and the substantial costs of implementing this technology amid a waning vCJD epidemic. Despite initial concerns of a second vCJD wave driven by non-MM individuals, there has been only one autopsy-confirmed case of clinical vCJD in an MV individual. Further, the high prevalence of PrPsc-positive appendices observed in the UK (1 in 2028 individuals in the Appendix-II study) may reflect dietary exposure to the bovine spongiform encephalopathy agent rather an ongoing, active infection. According to expert consensus, should a second wave occur, no more than a few cases may arise.
Summary/Conclusions: No cases of transfusion-associated vCJD have been reported since the adoption of universal leukodepletion in the UK in 1999. Furthermore, descriptive cohort studies and modeling studies suggest the risk of having a contaminated donation is minimal. Initial concerns of a second, more significant wave have yet to materialize despite the high prevalence of PrPsc-positive appendices in the UK. Therefore, the ongoing trend to reassess or (in some countries) fully withdraw vCJD deferral criteria seems justified and may significantly expand the donor base.
P089 Removal of UK-residence deferral for variant Creutzfeldt-Jakob disease: Impact on donor sufficiency in Australia
C Seed1, V Hoad1, H McManus2, P Kiely1, C Styles1, M Law2, J Kaldor2, I Gosbell1,3
1Donor and Product Safety Unit, Australian Red Cross Lifeblood, Melbourne, 2Kirby Institute, University of New South Wales, Sydney, 3School of Medicine, Western Sydney University, Penrith, Australia
Background: Until recently, Australian Red Cross Lifeblood indefinitely deferred people with prior residency in, or extended travel to, the UK during the risk period 1980–1996 (‘UK donors’) to mitigate the potential vCJD risk to blood safety. Regulatory approval to remove the deferral was underpinned by published (McManus, Vox Sanguinis 2022) mathematical modelling that concluded its removal would not increase the risk of vCJD transfusion-transmission beyond levels considered tolerable for blood safety. The modelling predicted a substantial sufficiency benefit, estimated at approximately 17,000 donors and 58,000 donations annually. The deferral was removed on 25 July 2022.
Aims: To analyse the sufficiency impact (additional donors and donations) of removing the deferral by tracking the donation metrics of the cohort of newly eligible UK donors, in the first 6-months after the policy change.
Methods: Lifeblood's donor questionnaire retained the UK deferral screening question until a version update effective from February 12, 2023. This permitted the identification of the cohort of newly eligible donors. Their donations were tracked for the period between 25 July 2022 and 24 January 2023 (6-month study period) and compared with baseline Lifeblood donation metrics and the modelled sufficiency predictions.
Results: A total of 38,462 UK donors attended to donate 78,762 times. Of these, 32,358 donors (females = 19,456, males = 12,902) successfully donated 67,916 times during the study period, representing 8.4% of the 804,830 total Lifeblood collections, at an average collection success rate of 86.2%. Of the 67,914 total donations excluding discards and autologous (n = 276), 40,108 were fresh blood and 27,530 were plasma donations for further manufacture. The trend of weekly donations by newly eligible UK donors showed an initial peak in the first 2 weeks (4020 and 3064 for weeks 1 and 2, respectively) with a subsequent stabilisation, maintaining high donations rates with a weekly average of 2866 in the last 2 weeks of the study period.
Summary/Conclusions: Cessation of the UK residence deferral for Australian donors has resulted in sufficiency gains well exceeding modelled predictions in the continuing absence of vCJD in Australia. In the first 6-months after the deferral was removed, the 67,914 additional fresh blood and plasma donations is more than double the predicted number, and if the trend at the end of the study period continues, will result in excess of 100,000 additional donations in the first year. The model assumed that UK donors would donate at rates proportional to that of the current donor base. However, the higher than modelled number of additional donations was expected because UK donors have factors associated with a higher rate of blood donation, such as higher education status. The additional donations occurred at a time when blood supplies were low due to ongoing COVID-19 pandemic impacts, and they helped avoid a potentially more significant blood shortage. If these newly eligible donors had not donated, donations would have been 88% of the inventory target; the additional collections allowed 96% of the inventory target to be achieved. The cohort of new and returned donors appear to be highly committed and have already made a substantial contribution to supporting both plasma for fractionation inventory, as well as local red blood cell and platelet inventories.
P193 Use of fresh frozen plasma, fibrinogen concentrate and cryoprecipitate in Ireland
A Farrelly1, B Doyle1, H Moloney1, T Hervig1
1Irish Blood Transfusion Service, Dublin, Ireland
Background: Based on the risk of transfusion transmitted vCJD, Irish plasma was removed as a therapeutic component over two decades ago. Following a review process in 2018, this decision was reversed. Considering the global shortage of Plasma Derived Medicinal Products (PDMPs), Ireland is now in a position to evaluate its contribution to the European supply of plasma, and move towards the use of Fresh Frozen Plasma (FFP) sourced from the Irish donor population.
The Irish Blood Transfusion Service (IBTS) has the sole responsibility for the distribution of fibrinogen concentrate and FFP in Ireland. The IBTS imports FFP (LG Octaplas™) and fibrinogen concentrate 1g (Riastap™) to supply Irish hospitals, which cater for a population of just over 5 million. Cryoprecipitate is prepared using Irish plasma and is used for paediatric surgery only. Ireland is currently collecting approximately 38,000L of whole blood derived recovered plasma, most of which is used for in vitro diagnostics.
Aims: This study is a retrospective, ten year review of the use of FFP, fibrinogen concentrate and cryoprecipitate in Ireland. This data can provide information on product usage in a country impacted by vCJD where alternative products were sourced to meet patients’ needs.
Methods: IBTS figures for total units distributed to hospitals were collated from 2012 to 2022, for Uniplas™, Octaplas™, LG-Octaplas™, Riastap™ and Cryoprecipitate.
Results: Comparing 2012 and 2022, the FFP usage decreased from 21,122 units to 17,340 units, a 17.9% reduction. Fibrinogen concentrate (1g) usage increased from 4683 to 8955 units, a 91.2% increase. Cryoprecipitate usage decreased from 161 to 83 units, a 48.4% decrease.
Summary/Conclusions: The use of fibrinogen concentrate has widely replaced cryoprecipitate, with the exception of very limited usage in some paediatric surgery. Fibrinogen concentrate usage saw the most significant change with a 91% increase in usage since 2012. Since 2016 demand for FFP has been approximately 17,000 units per year. Demand for FFP and fibrinogen concentrate reduced in 2020 during the first year of the COVID-19 pandemic, however, demand has since increased. Demand for cryoprecipitate has decreased steadily since 2017. This product is used only in particular paediatric surgeries. The IBTS is working towards re-introducing Irish plasma for therapeutic use, both as FFP and as plasma for fractionation to make PDMPs. The figures analysed in this study will help inform the future demand for plasma in the Republic of Ireland.
P195 Primary immunodeficiency patients exposed to UK-sourced immunoglobulin: Surveillance for asymptomatic carriage of abnormal prion protein
L Kanguru1, K Karekwaivanane1, S Lowrie1, K Ladhani2, J Cooper2, C Smith1, R Knight1
1National CJD Research & Surveillance Unit, UOE, Edinburgh, 2National Institute for Biological Standards & Control, South Mimms, United Kingdom
Background: Variant Creutzfeldt - Jakob disease (vCJD) is a very rare disease, associated with an abnormal form of prion protein. Most cases have been attributed to eating bovine spongiform encephalopathy (BSE) contaminated meat products. However, secondary transmission has occurred through blood transfusion and has been attributed, on one occasion, to treatment with a plasma product. Between 1996 and 2000, two intravenous immunoglobulin (Ig) products used to treat primary immunodeficiency diseases (PID) patients were manufactured from UK donor plasma-nine of these donors subsequently developed vCJD.
Aims: This study concerns the follow-up of patients exposed to these treatments to identify any case of vCJD, and, if found, to assess the likelihood of infection through this specific exposure.
Methods: Consenting patients had annual telephone and biennial face-to-face follow-up. Medical records were reviewed to identify any tissue and autopsy samples suitable for analysis. Blood samples were taken, anonymised and sent to the National Institute for Biological Standards and Control for storage pending possible future prion testing. PRNP-Codon 129 genotyping, histopathology, immunohistochemistry and PET blot analysis were undertaken. All cases are followed up to death or withdrawal.
Results: Of 79 cases included, none have yet shown symptoms or pathological evidence of vCJD. 58% were male, 70% born between 1960 and 1979, and 60% are still alive. The majority had a PID diagnosis of Common Variable Immunodeficiency (71%), and MM genotype (46%). The median time from first potential exposure to censor date was 20 years (range 8.9-28.2 years). Eight were known to have been treated with implicated batches (ones that included donations from pre-clinical vCJD donors), collectively contributing 155.1 person years of observation following first potential exposure. 46 cases donated 237 tissue specimens. Of these, 48 specimens from 22 cases were considered of sufficient quality (including from post-mortem). The average time from first exposure to specimen collection was 13.3 years (range 0-22.3 years). 7of the 21cases who have died underwent autopsy examination, with various causes of death, but not including vCJD: Aspiration pneumonia with disseminated carcinomatosis (1); Liver diseases (3); Alzheimer's disease/ cerebral amyloid angiopathy/progressive multifocal leucoencephalopthy (2); gastrointestinal haemorrhage of unknown cause (1).
Summary/Conclusions: We present the results of a follow-up study of patients with a potential exposure to vCJD infection via intravenous immunoglobulin products prepared from UK donor plasma, with some batches including donations from preclinical vCJD individuals. We found no evidence of transmission of vCJD, however, the incubation period from a potentially low dose exposure may be long. Uncertainties remain concerning the number of asymptomatic vCJD infections in the UK population, the risk of infection via blood components or plasma products derived from such individuals. The small number of vCJD cases, confirmed blood transmissions, and the absence of any vCJD transmission in this study is reassuring, and is evidence to support U.K. plasma being used in plasma product production. However continued surveillance for vCJD, and follow-up of these PID cases is important for public health confidence.
https://onlinelibrary.wiley.com/doi/full/10.1111/vox.13433?campaign=woletoc
Thursday, June 15, 2023
nvCJD or vCJD TSE PrP, and Blood, updated information
https://bloodprp.blogspot.com/2023/06/nvcjd-or-vcjd-tse-prp-and-blood-updated.html
FDA TSE Blood Ban
the old blood ban should have been updated to include sCJD, imo, considering now that cwd to humans is going to look like sporadic CJD, and we know that CWD Blood is transmissible. sCJD is not a single strain, but many strains, and the list is growing. and GSS blood has shown to transmit to monkey. we have another new livestock prion disease outbreak CMD camel prion disease that they have no clue about yet on zoonosis. the old belief of only nvCJD ever transmitting to anything, is just wishing thinking, more of the same, putting the cart before the horse safety protocol, imo. i will never give blood no matter what FDA et al says, until there is a test to show that my blood does not have PrPtse before donating, the risk is just to high still considering my mom died from the hvCJD, they just don't know enough about all the strains of sporadic cjd, or what about (vpspr?), and now two other strange atypical variants of the infamous sporadic CJDs. imo, science still out, so i choose not to risk any one else...
Successful transmission of the chronic wasting disease (CWD) agent to white-tailed deer by intravenous blood transfusion
Najiba Mammadova a b, Eric Cassmann a b, Justin J. Greenlee a
a Virus and Prion Research Unit, National Animal Disease Center, USDA, Agricultural Research Service, 1920 Dayton Avenue, Ames, IA 50010, USA
b Oak Ridge Institute for Science and Education (ORISE), USA
Received 7 May 2020, Revised 9 October 2020, Accepted 14 October 2020, Available online 16 October 2020, Version of Record 7 December 2020.
While a previous and larger study showed similar results, we determined that only 100 mL of CWD-infected blood (~2.5 times less than previously shown in (Mathiason et al., 2010)) contained sufficient levels of prion infectivity to cause disease. The identification of blood-borne transmission of the CWD agent is important in reinforcing the risk of exposure to CWD via blood as well as the possibility of hematogenous transmission of the CWD agent through insect vector. Finally, these results further highlight the importance of developing a sensitive and reproducible blood-based test to detect pre-clinical CWD, and warrant the continued advancement and evaluation of sensitive antemortem diagnostic tests for the detection of PrPSc in blood of asymptomatic cervids early in the incubation period.
https://www.sciencedirect.com/science/article/pii/S003452882031047X
https://bloodprp.blogspot.com/2021/06/cwd-tse-prion-zoonosis-transmission-to.html
Tuesday, June 28, 2022
Subclinical infection occurs frequently following low dose exposure to prions by blood transfusion
https://bloodprp.blogspot.com/2022/06/subclinical-infection-occurs-frequently.html
Wednesday, February 3, 2021
Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients
https://itseprion.blogspot.com/2021/02/wide-distribution-of-prion-infectivity.html
WEDNESDAY, SEPTEMBER 02, 2020
Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components Guidance for Industry
https://creutzfeldt-jakob-disease.blogspot.com/2020/09/recommendations-to-reduce-possible-risk.html
blood PrP 2021 - 2025
https://bloodprp.blogspot.com/
vCJD Blood Risk 2012 - 2015
https://vcjdblood.blogspot.com/
vCJD Transfusion Risk 2007 - 2015
https://vcjdtransfusion.blogspot.com/
vCJD or what was called nvCJD
https://vcjd.blogspot.com/
TSEAC
https://tseac.blogspot.com/
SEAC
https://seac992007.blogspot.com/
Creutzfeldt Jakob Disease CJD TSE prion
https://creutzfeldt-jakob-disease.blogspot.com/
VPSPr
https://vpspr.blogspot.com/
INFECTED BLOOD INQUIRY THE REPORT MAY 20, 2024
https://www.infectedbloodinquiry.org.uk/reports/inquiry-report
FOR anyone interested, you can see my old files from the early nvCJD blood scandal days, and the BSE Inquiry...terry
BSE Inquiry
https://www.infectedbloodinquiry.org.uk/sites/default/files/Volume-7.pdf
BSE Inquiry
Sunday, May 18, 2008 BSE, CJD, and Baby foods (the great debate 1999 to 2005)
http://bseinquiry.blogspot.com/2008/05/bse-cjd-and-baby-foods-great-debate.html
TUESDAY, AUGUST 1, 2017
BSE INQUIRY DFA 17 Medicines and medical devices
http://bseinquiry.blogspot.com/2017/08/bse-inquiry-dfa-17-medicines-and.html
Sunday, May 18, 2008
MAD COW DISEASE BSE CJD CHILDREN VACCINES
http://bseinquiry.blogspot.com/2008/05/mad-cow-disease-bse-cjd-children.html
http://bseinquiry.blogspot.com/2018/06/vaccines-tse-prion-risk-factors.html
MONDAY, MAY 19, 2008
SPORADIC CJD IN FARMERS, FARMERS WIVES, FROM FARMS WITH BSE HERD AND ABATTOIRS
http://bseinquiry.blogspot.com/2008/05/sporadic-cjd-in-farmers-farmers-wives.html
THURSDAY, JULY 22, 2010
BSE INQUIRY DFA 18 COSMETICS
http://bseinquiry.blogspot.com/2010/07/bse-inquiry-dfa-18-cosmetics.html
Sunday, May 18, 2008
BSE Inquiry DRAFT FACTUAL ACCOUNT DFA
BSE Inquiry DRAFT FACTUAL ACCOUNTS DFA's
http://bseinquiry.blogspot.com/2008/05/bse-inquiry-draft-factual-account-dfa.html
DFA 15 Monitoring and Enforcement of the SBO Specified Bovine Offal Regulations
http://bseinquiry.blogspot.com/2017/08/dfa-15-monitoring-and-enforcement-of.html
SATURDAY, AUGUST 26, 2017
DFA 14 Consideration of the Risk from Mechanically Recovered Meat (MRM) in 1989-1990
https://bseinquiry.blogspot.com/2017/08/dfa-14-consideration-of-risk-from.html
BSE INQUIRY DFA 16 MID 1995 TO THE FINAL DAYS
https://bseinquiry.blogspot.com/2017/08/bse-inquiry-dfa-16-mid-1995-to-final.html
BSE INQUIRY DFA
http://bseinquiry.blogspot.com/2012/04/wendy-grant-who-has-died-aged-89-was.html
nvCJD blood transfusion risks
https://vcjdblood.blogspot.com/
https://vcjdtransfusion.blogspot.com/
SEAC
https://seac992007.blogspot.com/
Singeltary Submission SEAC 2007
SEAC SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Minutes of the 99th meeting held on 14th December 2007 Singeltary Submission
This was 22 years to the day Mom died from the Heidenhain Variant of Creutzfeldt Jakob Disease i.e. hvCJD, when i made this submission to SEAC and this was their reply to my questions of concern about cjd in the USA, my how things have changed...terry
SEAC SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Minutes of the 99th meeting held on 14th December 2007
ITEM 8 – PUBLIC QUESTION AND ANSWER SESSION 40. The Chair explained that the purpose of the question and answer session was to give members of the public an opportunity to ask questions related to the work of SEAC. Mr Terry Singeltary (Texas, USA) had submitted a question prior to the meeting, asking: “With the Nor-98 now documented in five different states so far in the USA in 2007, and with the two atypical BSE H-base cases in Texas and Alabama, with both scrapie and chronic wasting disease (CWD) running rampant in the USA, is there any concern from SEAC with the rise of sporadic CJD in the USA from ''unknown phenotype'', and what concerns if any, in relations to blood donations, surgery, optical, and dental treatment, do you have with these unknown atypical phenotypes in both humans and animals in the USA? Does it concern SEAC, or is it of no concern to SEAC? Should it concern USA animal and human health officials?”
41. A member considered that this question appeared to be primarily related to possible links between animal and human TSEs in the USA. There is no evidence that sCJD is increasing in the USA and no evidence of any direct link between TSEs and CJD in the USA. Current evidence does not suggest that CWD is a significant risk to human health. There are unpublished data from a case of human TSE in the USA that are suggestive of an apparently novel form of prion disease with distinct molecular characteristics. However, it is unclear whether the case had been further characterised, if it could be linked to animal TSEs or if other similar cases had been found in the USA or elsewhere. In relation to the possible public health implications of atypical scrapie, H-type BSE and CWD, research was being conducted to investigate possible links and surveillance was in place to detect any changes in human TSEs. Although possible links between these diseases and human TSEs are of concern and require research, there is no evidence to suggest immediate public health action is warranted. The possible human health risks from classical scrapie had been discussed earlier in the meeting. Members noted that there are effective channels of discussion and collaboration on research between USA and European groups. Members agreed it is important to keep a watching brief on new developments on TSEs.
http://web.archive.org/web/20091010132933/http://www.seac.gov.uk/minutes/99.pdf
BLOODPRP UPDATED INFORMATION
https://bloodprp.blogspot.com/2024/03/transmissible-spongiform-encephalopathy.html
https://vcjd.blogspot.com/
Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk
Authors Lauren A. Crowder, Lawrence B. Schonberger, Roger Y. Dodd, Whitney R. Steele First published: 25 April 2017Full publication history DOI: 10.1111/trf.14145 View/save citation Cited by (CrossRef): 0 articles Check for updates Citation tools Funding Information
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
This work has been funded by Grant 2 U01 CK000360-03 from the US Centers for Disease Control and Prevention.
Abstract
BACKGROUND
Transfusion transmission of human prion diseases has been observed for variant Creutzfeldt-Jakob disease (vCJD), but not for the classic forms of prion disease (CJD: sporadic, genetic, and iatrogenic). Although the presence of prions or misfolded prion proteins in blood has been documented in some patients with the most common form of CJD, sporadic CJD, no transfusion-transmitted cases of CJD have been recognized. Since 1995, the American Red Cross has conducted a lookback study of the recipients of blood products from donors who develop CJD to assess the risk of blood-borne CJD transmission in the United States.
STUDY DESIGN AND METHODS
Blood donors subsequently diagnosed with confirmed or probable CJD were enrolled and the consignees were asked to identify the recipients of their blood products. These donors' transfusion recipients are traced annually with the National Death Index to see if they subsequently die of CJD.
RESULTS
To date, 65 CJD donors have been enrolled along with 826 of their blood recipients. These recipients have contributed 3934 person-years of follow-up and no transfusion-transmitted cases of CJD have been recognized.
CONCLUSION
From this study, as well as other epidemiologic studies, there is no evidence of CJD transfusion transmission; this risk remains theoretical.
http://onlinelibrary.wiley.com/doi/10.1111/trf.14145/abstract?campaign=wolearlyview
SUNDAY, MARCH 09, 2014
A Creutzfeldt-Jakob Disease (CJD) Lookback Study: Assessing the Risk of Blood Borne Transmission of Classic Forms of Creutzfeldt-Jakob Disease
http://creutzfeldt-jakob-disease.blogspot.com/2014/03/a-creutzfeldt-jakob-disease-cjd.html
SATURDAY, DECEMBER 08, 2007
Transfusion Transmission of Human Prion Diseases
http://vcjdblood.blogspot.com/2007/12/transfusion-transmission-of-human-prion.html
Tuesday, November 29, 2016
Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: new insights into the molecular underpinnings of prion infectivity
http://transmissiblespongiformencephalopathy.blogspot.com/2016/11/transmissibility-of-gerstmannstraussler.html
2017, please note concern, a few recent studies...kindest regards, terry
In summary, PrPsc was detectable at high levels in organs and tissues of the LRS only in BSE/vCJD infected animals (0.1% to 10% of the amounts found in the brains of the same animals). We interpreted these results as the BSE prion being highly lymphotropic in primates. These findings correlated indeed with the tonsils, spleens and appendices of vCJD patients being found positive for PrPsc18,19,20). We therefore proposed that LRS tissues be considered ‘high-risk’ in vCJD patients only.
However, lower amounts of PrPsc were detected in adrenals, muscles and intestinal tissue of macaques infected with BSE/vCJD as well as sCJD and iCJD, associated with peripheral nerves. Levels were less than 10,000 times lower than brain PrPres levels (<0.001%).
*** We therefore proposed that these tissues be considered “low-risk” for all CJD patients.
see ;
Review Modeling Variant Creutzfeldt-Jakob Disease and Its Pathogenesis in Non-human Primates Corinne Lasmézas1)
1) Scripps Florida, 130 Scripps Way, Jupiter FL 33458, USA
Released 20170330 Received 20170123 Accepted 20170209
Keywords: prions, variant Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, non-human primates, transmission, pathogenesis, blood Full Text PDF [7720K] Corresponding author: Corinne Lasmézas, Scripps Florida, 130 Scripps Way, Jupiter FL 33458, USA (E-mail: lasmezas (at) scripps.edu) The contents of this article reflect solely the view of the author(s).
Conflict of interest statement: The authors had no conflicts of interest to declare in this article.
This paper was presented at the Animal Prion Diseases Workshop “Updated Diagnosis and Epidemiology of Animal Prion Diseases for Food Safety and Security” supported by the OECD Co-operative Research Programme. (See “Food Safety” Vol.4 (2016), No.4, 103-4.)
Abbreviations: BSE: Bovine Spongiform Encephalopathy; CNS: central nervous system; iCJD: iatrogenic Creutzfeldt-Jakob disease; IV: intravenous; LN: lymph nodes; LRS: lymphoreticular system; PrPsc: disease-associated prion protein; RBCs: red blood cells; sCJD: sporadic Creutzfeldt-Jakob disease; TSEs: transmissible spongiform encephalopathies; vCJD: variant Creutzfeldt-Jakob disease
Index
Abstract 1. Transmission of Bovine Spongiform Encephalopathy (BSE) to CynomolgusMacaques Reproduces vCJD: Establishment of a non-human Primate Model for vCJD 1.1. BSE, a New Disease in Cattle 1.2. vCJD in Humans and Transmission of BSE to Non-human Primates 1.3. Determination of the Minimal Infectious BSE Dose in Non-human Primates 1.4. Adaptation of the BSE Agent to Non-human Primates: Consequences for Human Health 2. The Cynomolgus Macaque as a model to Understand the Pathogenesis of Variant Creutzfeldt-Jakob Disease (vCJD) and Model Risk of Interhuman Transmission 2. 1. Distribution of Prions in Tissues and Organs of BSE/vCJD Macaques after Oral or Intravenous (IV) Inoculation 2. 2. Distribution of Prions in Tissues and Organs of vCJD, Sporadic and Iatrogenic CJD Infected Macaques 2.2. Blood Infectivity Studies in the Macaque vCJD Model Acknowledgments References Abstract In the early 90s’, Europe was shaken by the fear that the prions from “mad cow disease” (bovine spongiform encephalopathy) would transmit the disease to humans via beef products. In 1996, the first variant Creutzfeldt-Jakob (vCJD) patients were described, and the same year our Bovine Spongiform Encephalopathy (BSE) transmission studies to cynomolgus macaques demonstrated that the BSE prion was highly infectious for primates, inducing brain lesions identical to those observed in vCJD patients. These studies provided the first experimental evidence that vCJD was BSE in humans. Subsequent studies established the BSE/vCJD-infected cynomolgus macaque as a robust model to study the pathogenesis of vCJD.
see ;
Review Modeling Variant Creutzfeldt-Jakob Disease and Its Pathogenesis in Non-human Primates Corinne Lasmézas1)
1) Scripps Florida, 130 Scripps Way, Jupiter FL 33458, USA
Released 20170330 Received 20170123 Accepted 20170209
Keywords: prions, variant Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, non-human primates, transmission, pathogenesis, blood Full Text PDF [7720K] Corresponding author: Corinne Lasmézas, Scripps Florida, 130 Scripps Way, Jupiter FL 33458, USA (E-mail: lasmezas (at) scripps.edu) The contents of this article reflect solely the view of the author(s).
Conflict of interest statement: The authors had no conflicts of interest to declare in this article.
This paper was presented at the Animal Prion Diseases Workshop “Updated Diagnosis and Epidemiology of Animal Prion Diseases for Food Safety and Security” supported by the OECD Co-operative Research Programme. (See “Food Safety” Vol.4 (2016), No.4, 103-4.)
Abbreviations: BSE: Bovine Spongiform Encephalopathy; CNS: central nervous system; iCJD: iatrogenic Creutzfeldt-Jakob disease; IV: intravenous; LN: lymph nodes; LRS: lymphoreticular system; PrPsc: disease-associated prion protein; RBCs: red blood cells; sCJD: sporadic Creutzfeldt-Jakob disease; TSEs: transmissible spongiform encephalopathies; vCJD: variant Creutzfeldt-Jakob disease
Index
Abstract 1. Transmission of Bovine Spongiform Encephalopathy (BSE) to CynomolgusMacaques Reproduces vCJD: Establishment of a non-human Primate Model for vCJD 1.1. BSE, a New Disease in Cattle 1.2. vCJD in Humans and Transmission of BSE to Non-human Primates 1.3. Determination of the Minimal Infectious BSE Dose in Non-human Primates 1.4. Adaptation of the BSE Agent to Non-human Primates: Consequences for Human Health 2. The Cynomolgus Macaque as a model to Understand the Pathogenesis of Variant Creutzfeldt-Jakob Disease (vCJD) and Model Risk of Interhuman Transmission 2. 1. Distribution of Prions in Tissues and Organs of BSE/vCJD Macaques after Oral or Intravenous (IV) Inoculation 2. 2. Distribution of Prions in Tissues and Organs of vCJD, Sporadic and Iatrogenic CJD Infected Macaques 2.2. Blood Infectivity Studies in the Macaque vCJD Model Acknowledgments References Abstract In the early 90s’, Europe was shaken by the fear that the prions from “mad cow disease” (bovine spongiform encephalopathy) would transmit the disease to humans via beef products. In 1996, the first variant Creutzfeldt-Jakob (vCJD) patients were described, and the same year our Bovine Spongiform Encephalopathy (BSE) transmission studies to cynomolgus macaques demonstrated that the BSE prion was highly infectious for primates, inducing brain lesions identical to those observed in vCJD patients. These studies provided the first experimental evidence that vCJD was BSE in humans. Subsequent studies established the BSE/vCJD-infected cynomolgus macaque as a robust model to study the pathogenesis of vCJD.
We showed rapid adaptation of BSE prions to primates upon subsequent passage, and their distribution in peripheral tissues and blood. Some key studies are summarized in the present paper.
Page top 1. Transmission of Bovine Spongiform Encephalopathy (BSE) to Cynomolgus Macaques Reproduces vCJD: Establishment of a non-human Primate Model for vCJD 1.1. BSE, a New Disease in Cattle In 1987, a new prion disease affecting dairy cattle was described in the United Kindom1). Affected cows presented signs of aggressiveness, anxiety, ataxia and were finally found recumbent. The disease was rapidly classified in the group of “transmissible spongiform encephalopathies”, or TSEs, due to the transmissibility of the disease2), as well as the similarities of the neuropathological lesions and molecular hallmark with those found in sheep scrapie and human CJD: neuronal death, spongiform changes, and accumulation of misfolded and aggregated prion protein (termed PrPsc)3). PrPsc is the infectious form of the host prion protein PrP. It is also called a prion (for “proteinaceaous infectious particle4)) or TSE agent. The number of affected cows increased rapidly to top at a 37,280 diagnosed animals in the year of 1992 (OIE data). Thankfully, British epidemiologists recognized that BSE was due to the consumption of prion-tainted meat and bone meal (MBM)5), and the first feed-ban was implemented in 1988, prohibiting the feeding of ruminants with ruminant-derived MBM.
1.2. vCJD in Humans and Transmission of BSE to Non-human Primates In 1991, BSE was reported in a domestic cat that presumably was contaminated via pet food6). Transmission of scrapie from small ruminants to cats had never been described, raising concern that BSE might be more pathogenic than scrapie not only for cats, but also for humans. In order to probe the cow-to-primates species barrier of the BSE agent, we inoculated cynomolgus macaques (Macaca fascicularis) with BSE-infected cow brains at the French Atomic Energy Commision (CEA).
In 1996, 10 young individuals were described in the UK and one in France, harboring an unusual form of CJD that was coined variant CJD (vCJD)7,8). Besides patients being exceptionally young (adolescents and young adults, while sporadic CJD (sCJD) affects people over the age of 60), they exhibited unusual symptoms. Early symptoms were dysaesthesia, behavioral symptoms, depression, ataxia, with myoclonus appearing later on, contrasting with the cognitive course of the disease (memory impairment, dementia) preceding motor impairment, which is most frequently observed in sCJD. Moreover, vCJD patients presented specific neuropathological features with spongiosis and neuronal loss most evident in the basal ganglia and thalamus, and the presence of PrP amyloid plaques (abundant in the cerebral cortex and cerebellum) that were surrounded by vacuoles, giving them a flower-like appearance. These peculiar plaques were called florid plaques7).
At the same time as the first vCJD patients were being described, we were examining the brains of our 3 macaques that had all come down with disease 3 years after intracerebral (IC) inoculation with BSE-infected cow brain. Clinical signs were characterized by behavioral signs such as depression or edginess, as well as truncal ataxia (broad-based gait, tremors) and myoclonus. Neuropathological examination of the brains of the BSE-macaques revealed the presence of florid plaques and other neuropathological features similar to those observed in vCJD patients (Fig. 1). Florid plaques were not present in the brains of macaques inoculated with Kuru or sCJD, and thus were considered specific for infection by the BSE prion. Moreover, PrPsc in BSE-infected macaques and vCJD patients exhibited a similar electrophoretic pattern by western blot (Fig. 1).
In summary, macaques infected by BSE reproduced the behavioral and motor symptoms, the neuropathology and the biochemical signature of vCJD in humans. This study provided the first experimental evidence supporting that vCJD was due to human infection by the BSE agent9), and an experimental model to study the new disease.
1.3. Determination of the Minimal Infectious BSE Dose in Non-human Primates
In a concerted European effort involving 5 laboratories including ours, the BSE-macaque model was then used to evaluate the minimal amount of BSE-infected material necessary to induce vCJD in primates. Results so far show that 5g of infectious BSE cattle brain is sufficient to induce the disease in all recipient animals by the oral route, with 500 mg yielding an incomplete attack rate10,11). The ID50 of BSE cattle brain is 200 mg for cattle12). These results suggest a low species barrier between cattle and non-human primates.
1.4. Adaptation of the BSE Agent to Non-human Primates: Consequences for Human Health
The macaque BSE model provided an opportunity to evaluate the possible risk for humans of secondary inter-human transmission of the BSE/vCJD prion. Accidental human-to-human transmissions of sCJD, resulting in iatrogenic CJD (iCJD) has occurred in several unfortunate circumstances (described in ref.13). One of them was the infection of children with CJD-contaminated human growth hormone (hGH) extracted from cadaveric hypophyses. These iCJD patients had been treated for short stature by injection of hGH in childhood, and 226 of them died of iCJD as young adults, mainly in France and the USA13). Other dramatic iCJD cases had been linked to the surgical implantation of dura-mater grafts, resulting in 228 deaths13). A few cases were also due to corneal grafts and intracranial electrodes. Although all known iCJD cases prior to 2004 had been linked to contamination with central nervous system (CNS) tissue, the possibility existed that the BSE agent would harbor a different distribution in primates than the sCJD agent, thus representing a higher risk of transmission via organ/tissue grafts, contamination of surgical instruments or even blood transfusion.
As a first step for risk assessment, we transmitted the BSE prion from macaque to macaque via different routes. We also established a dose-response (incubation time) for the IC route to provide a baseline for subsequent infectivity measurement studies. This experiment showed that the BSE agent adapts rapidly to primates, as incubation periods shortened from 3 to 1.5 years upon secondary passage at the highest dose14). It also showed that, for a given amount of BSE material (40 mg BSE brain homogenate), the incubation period was the same whether inoculation was done by the IC or the intravenous (IV) route.
2. The Cynomolgus Macaque as a model to Understand the Pathogenesis of Variant Creutzfeldt-Jakob Disease (vCJD) and Model Risk of Interhuman Transmission
2. 1. Distribution of Prions in Tissues and Organs of BSE/vCJD Macaques after Oral or Intravenous (IV) Inoculation
We compared second passage macaques inoculated with BSE prions by the oral or IV routes15). PrPsc was detected by immunohistochemistry and by ELISA after “scrapie associated fibril” (SAF) purification15). In addition to the brain, we detected PrPsc in spleen, tonsils, intestine and sciatic nerve in amounts that did not depend on the inoculation route, with the exceptions of the spleen where PrPsc amounts were up to 4% the amounts found in the brain after IV inoculation, and up to 0.2% those of the brain after oral dosing15).
2. 2. Distribution of Prions in Tissues and Organs of vCJD, Sporadic and Iatrogenic CJD Infected Macaques
We also infected macaques with vCJD, sCJD, iCJD16). As determined earlier, BSE and vCJD prions correspond to the same prion strain, and one or the other denomination is used depending on the species of origin for the brain tissue used as inoculum. All prion strains were inoculated in the same manner (intracerebral and intratonsillar combined), in order to be able to directly compare tissue distribution of PrPsc between strains.
Disease-associated PrP deposits were detected by immunocytochemistry in various organs. They were found in the Peyer’s patches of the gut and other lymphoreticular system (LRS) tissue of BSE/vCJD infected animals (Fig. 2). By PET-blot, we showed that these deposits corresponded to proteinase K-resistant PrP, a biochemical subset of PrPsc. Interestingly, not all Peyer’s patches of a single animal were PrPsc positive (Fig. 2), showing that PrPsc-negative LRS tissue biopsies may lead to false negative diagnostic results.
Pathological PrP deposits were also detected in the enteric nervous system in macaques infected with all prion strains. Fig. 3 shows the localization of pathological PrP in the pericarya of neurons of the myenteric plexus, as well as in small nerve fibers of the inner muscular layer of the intestine.
Pathological PrP deposits were also found in peripheral nerves and in muscle for all CJD strains (Table 1). In the peripheral nerves, they were found mostly at the surface of Schwann cells (Fig. 4). In muscle, they were localized to specific foci in the vicinity of nerve fibers (Fig. 5). Our results suggest that the heterogeneous, patchy distribution of pathological PrP deposits in muscles corresponds to the distribution zones of motor end plates. This study provides a possible explanation for the variably positive detection of pathological PrP in muscle samples of sCJD patients17).
PrPsc amounts were also measured semi-quantitatively using a sensitive biochemical detection method including phosphotungstic acid precipitation as a concentration method, and western blot or ELISA detection16). This method revealed the presence of PrPsc in the spleen of the sCJD infected macaque and tonsils of the iCJD infected macaque, but no PrPsc could be detected in lymph nodes and Peyer’s patches of these animals, a result most likely due to the presence of PrPsc amounts at the threshold of detection in the LRS of sCJD and iCJD macaques, and sampling variations. These results are summarized in Table 1.
In summary, PrPsc was detectable at high levels in organs and tissues of the LRS only in BSE/vCJD infected animals (0.1% to 10% of the amounts found in the brains of the same animals). We interpreted these results as the BSE prion being highly lymphotropic in primates. These findings correlated indeed with the tonsils, spleens and appendices of vCJD patients being found positive for PrPsc18,19,20). We therefore proposed that LRS tissues be considered ‘high-risk’ in vCJD patients only.
However, lower amounts of PrPsc were detected in adrenals, muscles and intestinal tissue of macaques infected with BSE/vCJD as well as sCJD and iCJD, associated with peripheral nerves. Levels were less than 10,000 times lower than brain PrPres levels (<0.001%). We therefore proposed that these tissues be considered “low-risk” for all CJD patients.
Our results expanded upon observations made in vCJD patients that PrPsc is detectable in tonsils, emphasizing that BSE prions are largely lymphotropic in primates, and may replicate in lymph notes, tonsils, spleen and Peyer’s patches before the symptomatic phase. Our subsequent studies confirmed that lymph node biopsies of BSE-inoculated macaques were positive for PrPsc prior to the onset of clinical signs (see below). In another study, gut-associated lymphoid tissue and gut-draining lymph nodes were found positive for PrPsc within one year of oral infection of macaques with cattle BSE21). On the other hand, distribution of PrPsc in muscle of macaques inoculated with vCJD, sCJD and iCJD suggests a centrifugal spread of prions from the CNS to muscle motor plates via motor nerves, occurring after CNS invasion by prions. In addition, it is probable that centripetal spread of prions via peripheral nerves also occurs in earlier stages of infection stochastically from various points of entry, even in the absence of prior LRS replication. We demonstrated this paradigm earlier in severely immunodeficient (SCID) mice infected with mouse-adapted scrapie22). Moreover, spread from the gut to the CNS via autonomic nerve fibers has been shown in experimental scrapie and BSE23,24,25). Fig. 6 illustrates the distribution and proposed propagation of prions in our non-human primate model.
2.2. Blood Infectivity Studies in the Macaque vCJD Model The lymphotropic properties of BSE prions raised the important question of the presence of infectivity in blood of vCJD patients.
We initiated a large blood transfusion study where whole blood, white blood cells or plasma from either vCJD patients or BSE/vCJD macaques was injected by IV or IC to recipient macaques. This experiment led to most macaques surviving over prolonged periods of time (>10 years), and few coming down with BSE/vCJD or intercurrent illnesses. These studies continued after the author of this manuscript left the CEA. Interim transmission results are shown in Fig. 7, and some important observations were as follows. Blood depleted for red blood cells (RBC) from a vCJD patient (7.5 mL) injected intravenously did not result in any clinical disease in the recipient macaque after 10 years, yet this animal harbored positive IHC staining in the inguinal lymph nodes (LNs). Another macaque, who had received 25 mL of RBC-depleted blood intravenously from another vCJD patient, died suddenly at 42 months after inoculation, and harbored PrPsc positive inguinal LNs. Two other animals, that received 500 µL of buffy coat (BC) from vCJD patients by IC, were still alive 10 years after inoculation (with PrPsc positive LNs, Fig. 7A). A whole blood transfusion of 40 mL from a vCJD macaque (who died 3 years after intracerebral + intratonsillar inoculation of human vCJD brain homogenate) induced clinical signs of vCJD in the recipient macaque 66 months after the transfusion. Inguinal lymph nodes biopsies had been positive since 45 months, i.e. 75% of the incubation period (Fig. 7B). Other macaques transfused with blood from BSE-macaques survived more than 10 years, but some had positive LNs (Fig. 7C). Another notable result was the transmission of BSE infection by the plasma from a macaque that had been dosed orally with cattle BSE 27.5 months earlier. The donor macaque died with a behavioral syndrome of self-injury 117 months after challenge with a diagnosis of probable BSE, hence infectivity was present in its blood at a quarter of the incubation period (Fig. 7D).
In 2004, the first transfusion-related case of vCJD was described in a patient who had been transfused with non-leucoreduced red blood cells from a donor who developed vCJD 3.5 years after the donation26). A total of four transfusion-related vCJD transmissions have been reported to date27).
Acknowledgments
I thank the many people who supported and participated in this work at the CEA: Dominique Dormont, Jean-Philippe Deslys, Christian Herzog, Nathalie Lescoutra, Nicole Salès, Emmanuel Comoy, René Rioux. I also thank Ray Bradley and Michael Dawson for providing BSE-infected cattle brain homogenates. I am thankful to Robert Will and Nicolas Kopp for providing vCJD samples, and to James Ironside for his collaboration on the neuropathology of BSE-infected macaques. I am grateful to my European collaborators Maurizio Pocchiari, Gerhard Hunsmann, Johannes Löwer, Pär Bierke, Loredana Ingrosso, Uwe Hahmann, Dirk Motzkus, Edgar Holznagel, for their friendship and for embarking on this challenging project.
https://www.jstage.jst.go.jp/article/foodsafetyfscj/5/1/5_2016034/_html
https://www.jstage.jst.go.jp/article/foodsafetyfscj/5/1/5_2016034/_pdf
Volume 23, Number 6—June 2017 Synopsis
Sporadic Creutzfeldt-Jakob Disease in 2 Plasma Product Recipients, United Kingdom, P. Urwin et al.
View Summary
Two cases of sporadic CJD with clotting disorders have been identified, but this may represent a chance event.
https://wwwnc.cdc.gov/eid/ahead-of-print
Volume 23, Number 6—June 2017
Research
Distribution and Quantitative Estimates of Variant Creutzfeldt-Jakob Disease Prions in Tissues of Clinical and Asymptomatic Patients
Jean Y. Douet, Caroline Lacroux, Naima Aron, Mark W. Head, Séverine Lugan, Cécile Tillier, Alvina Huor, Hervé Cassard, Mark Arnold, Vincent Beringue, James W. Ironside, and Olivier Andréoletti
Comments to Author Author affiliations: Institut National de la Recherche Agronomique, Toulouse, France (J.Y. Douet, C. Lacroux, N. Aron, S. Lugan, C. Tillier, A. Huor, H. Cassard, O. Andréoletti); University of Edinburgh, Edinburgh, Scotland, UK (M.W. Head, J.W. Ironside); Animal and Plant Health Agency, Loughborough, UK (M. Arnold); Institut National de la Recherche Agronomique, Jouy-en-Josas, France (V. Beringue) Suggested citation for this article
Abstract
In the United-Kingdom, ≈1 of 2,000 persons could be infected with variant Creutzfeldt-Jakob disease (vCJD). Therefore, risk of transmission of vCJD by medical procedures remains a major concern for public health authorities. In this study, we used in vitro amplification of prions by protein misfolding cyclic amplification (PMCA) to estimate distribution and level of the vCJD agent in 21 tissues from 4 patients who died of clinical vCJD and from 1 asymptomatic person with vCJD. PMCA identified major levels of vCJD prions in a range of tissues, including liver, salivary gland, kidney, lung, and bone marrow. Bioassays confirmed that the quantitative estimate of levels of vCJD prion accumulation provided by PMCA are indicative of vCJD infectivity levels in tissues. Findings provide critical data for the design of measures to minimize risk for iatrogenic transmission of vCJD.
snip...
Discussion
Most previous studies with tissue from vCJD patients have failed to identify consistent accumulation of the vCJD agent outside the nervous and lymphoreticular systems. However, data obtained in this study clearly demonstrate the presence of vCJD prions in a wide and unexpected variety of peripheral tissues.
Natural scrapie and experimental BSE in sheep are 2 models of orally transmitted prion diseases (24,25). In both diseases, the agent accumulates in the lymphoreticular system and the enteric nervous system during the early preclinical phase of the incubation period. Moreover, an early and persistent prionemia is observed in asymptomatic infected animals (26,27). These features were also observed in vCJD in humans and in view of the likely origin of vCJD (oral exposure to BSE agent), these similarities have led to a consensus that BSE and scrapie in sheep and vCJD in human have a common pathogenesis (28).
Although vCJD prions in a variety tissues, such as bone marrow, kidney, salivary gland, skeletal muscle, pancreas, liver, or heart, might be surprising, each of these tissue has already been demonstrated to accumulate prion infectivity or abnormal prion protein in TSE-infected sheep (29–33). Because low levels of infectivity have been reported in blood fractions from a vCJD-affected patient, such widespread tissue positivity might be derived from residual blood, rather than from the solid tissue in these samples (16). However, this proposal seems unlikely because in whole blood PMCA amplification inhibitors preclude detection of endogenous vCJD agent by this method (11,34–36).
The patient in our study who was infected with a prion containing PRNP gene codon 129 Met/Val is 1 of only 2 identified vCJD agent–infected persons known to have died of other causes before onset clinical symptoms of vCJD, and the only person who provided consent to sample autopsy tissues for research. For this patient, all previous investigations did not detect abnormal prion protein or infectivity in the brain (12,37). The negative PMCA results we obtained for cerebral cortex, dorsal root ganglia, and trigeminal ganglia tissue from this patient are consistent with a lack of central nervous system involvement at the time of death. However, PMCA seeding activity in the pituitary gland was surprising in this instance.
The presence of abnormal prion protein accumulation in the pituitary gland and other circumventricular organs before deposition of PrPres in surrounding brain has been reported in TSE-infected sheep (38). However, this phenomenon in animals does not represent the main route for neuroinvasion and is a probable consequence of hematogenous dissemination of the TSE agent through the fenestrated capillary system of the circumventricular organs, which is substantially more permeable than the other capillaries in the brain (blood–brain barrier). Therefore, this finding might be a consequence of the hematogenous route of secondary vCJD in this person (by transfusion of packed erythrocytes from a vCJD-infected donor), in contrast to the oral route of infection in primary clinical vCJD cases (12).
vCJD prions were detected in certain peripheral tissues from the patients infected with a prion containing the PRNP gene codon 129 Met/Val. Although distribution of vCJD seeding activity in lymphoreticular tissues was similar to that observed for symptomatic vCJD patients, several tissues that were positive in clinically affected patients were negative in this heterozygous asymptomatic person. These findings suggest that involvement of some peripheral tissues might occur at a later stage in the incubation period than others, or that they could involve recirculation of the agent from the central nervous system (i.e., centrifugal spread in a late state). However, we cannot discount the possibility that that these differences in tissue distribution are caused by the hematogenous route of infection in this person (as opposed to the probable oral route in patients with clinical vCJD) or the difference between the PRNP gene codon 129 genotype of the asymptomatic vCJD–affected person (PRNP gene codon 129 Met/Val) and persons with clinical vCJD (PRNP gene codon 129 Met/Met).
Irrespective of the actual explanation for these differences, the presence of vCJD agent in peripheral tissues of patients during preclinical and clinical stage of the disease indicates the potential for iatrogenic transmission of this fatal neurologic condition by surgical procedures. Furthermore, this finding shows that, for certain peripheral tissues, a level of infectivity equivalent to an end stage titer (and attendant risk) is reached at a preclinical stage.
Several hundred cases of iatrogenic CJD have been reported worldwide. These cases appear to result from transmission of sporadic CJD, and most cases have occurred in recipients of human dura mater grafts or after administration of human growth hormone extracted from cadaveric pituitaries (39). Although in sporadic CJD the distribution of the agent is largely restricted to the nervous system (central and peripheral), the wide distribution of the vCJD agent in the asymptomatic infected patient we report might serve to increase the range of medical procedures, including dentistry, organ transplant, and surgery involving nondisposable equipment, that might result in iatrogenic transmission of vCJD (40–43).
Nevertheless, >20 years after identification of the first vCJD patients, only 5 cases that are a probable consequence of iatrogenic vCJD transmission are known, all in the United Kingdom and associated with blood and blood products. These cases were caused by transfusion of non–leukocyte-depleted erythrocyte concentrates or by treatment involving large amounts of pooled plasma from the United Kingdom that were known to include donations from persons who later showed development of vCJD (12,44–46).
None of the 220 other vCJD cases identified worldwide have been linked to any other medical or dental procedure. Whereas this fact is reassuring, it would be unwise to disregard the threat that vCJD still poses for public health. Despite the relatively low number (n = 178) of vCJD clinical cases observed in the United Kingdom, the most recent epidemiologic studies indicate that ≈1 of 2,000 persons in the United Kingdom could be infected with the vCJD agent (as indicated by the presence of abnormal prion protein detected by immunohistochemical analysis of lymphoid follicles in the appendix). Each asymptomatic vCJD-infected person represents a potential source of secondary infection. The data in our report offer an opportunity for refining measures that were implemented in many countries to limit the risk for vCJD iatrogenic transmission. The apparent concordance between PMCA biochemical and infectivity bioassay data, and the higher analytical sensitivity of PMCA, suggest that future research need not rely exclusively on time-consuming and costly animal bioassay.
Our results indicate the need for vCJD screening assays. After more than a decade of effort, several vCJD blood detection tests have reached a stage in their development that could enable their evaluation as screening or confirmatory assays (11,47,48). In particular, there is now a strong case for use of PMCA in a highly sensitive and specific blood test for vCJD, as indicated by our previous studies (11,16) and studies by Bougard et al. (35) and Concha-Marambio et al. (36). The relationship shown here between PrPres amplification by PMCA and detection of infectivity by bioassay indicates that PMCA seeding activity is a good surrogate marker of infectivity and could provide a sound basis for a vCJD blood test for use with blood or tissue donors.
Dr. Douet is a research scientist and assistant lecturer in ophthalmology at the National Veterinary School of Toulouse, Toulouse, France. His primary research interests are the pathogenesis of the prion disease with special emphasis on the iatrogenic risk of transmission.
Acknowledgment
This study was supported in part by the Department of Health Policy Research Programme and the Scottish Government. The National CJD Research and Surveillance Unit is supported by the Policy Research Program of the Department of Health and the Scottish Government (DH121/5061). The Edinburgh Brain Bank is supported by the Medical Research Council (MRC grant G0900580). The Unité Mixte de Recherche 1225, Ecole Nationale Vétérinaire de Toulouse was supported by the European Union FEDER/INTERREG (EFA282/13 TRANSPRION), the Institut National de la Recherche Agronomique Institut Carnot en Santé Animale, and an Agence Nationale Recherche grant (Unmasking Blood Prions; ANR-15-CE18-0028).
https://wwwnc.cdc.gov/eid/article/23/6/16-1734_article
MONDAY, NOVEMBER 23, 2015
Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study ORIGINAL RESEARCH
Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study
Diane L. Ritchie1,*, Susan V. Gibson2,†, Christian R. Abee3, Thomas R. Kreil4, James W. Ironside1 and Paul Brown5
Article first published online: 23 NOV 2015
DOI: 10.1111/trf.13422
© 2015 AABB
Issue
Cover image for Vol. 55 Issue 11
Transfusion
Early View (Online Version of Record published before inclusion in an issue)
Abstract
BACKGROUND
Four secondary transmissions of variant Creutzfeldt-Jakob disease (vCJD) infectivity have been associated with the transfusion of nonleukoreduced red blood cells collected from vCJD patients during the asymptomatic phase of the disease. Establishing efficient experimental models for assessing the risk of future transmissions of vCJD infectivity via blood transfusion is of paramount importance in view of a study of archived appendix samples in which the prevalence of asymptomatic vCJD infection in the United Kingdom was estimated at approximately 1 in 2000 of the population. In this study, we investigated transmission of vCJD and sporadic CJD (sCJD) infectivity from blood using the squirrel monkey, which is highly susceptible to experimental challenge with human prion disease.
STUDY DESIGN AND METHODS
Whole blood collected from vCJD- and sCJD-infected squirrel monkeys was transfused at multiple time points into recipient squirrel monkeys. Blood recipients were euthanized approximately 7 years after their first blood transfusion.
RESULTS
No clinical or pathologic signs of a prion disease were observed in either the sCJD- or the vCJD-transfused monkeys, and immunohistochemistry and biochemical investigations showed no PrPTSE in central nervous system or lymphoreticular tissues. Similarly, monkeys inoculated intracerebrally (IC) and intravenously (IV) with either buffy coat or plasma from vCJD and sCJD patients failed to develop disease. However, white blood cells from a chimpanzee-passaged strain of human Gerstmann-Sträussler-Scheinker (GSS) disease transmitted autopsy-proven disease to two IC-inoculated monkeys after incubation periods of 34 and 39 months.
CONCLUSION
Blood transmits GSS but not sCJD or vCJD infectivity to IC- or IV-inoculated squirrel monkeys within a 7-year observation period.
http://onlinelibrary.wiley.com/doi/10.1111/trf.13422/abstract
2015 PRION CONFERENCE
*** RE-P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study
***suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. ***
P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study
Paul Brown1, Diane Ritchie2, James Ironside2, Christian Abee3, Thomas Kreil4, and Susan Gibson5 1NIH (retired); Bethesda, MD USA; 2University of Edinburgh; Edinburgh, UK; 3University of Texas; Bastrop, TX USA; 4Baxter Bioscience; Vienna, Austria; 5University of South Alabama; Mobile, AL USA
Five vCJD disease transmissions and an estimated 1 in 2000 ‘silent’ infections in UK residents emphasize the continued need for information about disease risk in humans. A large study of blood component infectivity in a non-human primate model has now been completed and analyzed. Among 1 GSS, 4 sCJD, and 3 vCJD cases, only GSS leukocytes transmitted disease within a 5–6 year surveillance period. A transmission study in recipients of multiple whole blood transfusions during the incubation and clinical stages of sCJD and vCJD in ic-infected donor animals was uniformly negative. These results, together with other laboratory studies in rodents and nonhuman primates and epidemiological observations in humans, suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. The issue of decades-long incubation periods in ‘silent’ vCJD carriers remains open.
https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf
ran across an old paper from 1984 ;
***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent. ***
http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html
From: Terry S. Singeltary Sr.
Sent: Saturday, November 15, 2014 9:29 PM
To: Terry S. Singeltary Sr.
Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984
THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL
1984
snip...
http://web.archive.org/web/20050425210551/http://www.bseinquiry.gov.uk/files/mb/m26/tab01.pdf
THE BAXTER STUDY...SEE MORE HERE ;
http://tseac.blogspot.com/2009/09/tseac-meeting-february-12-2004-baxter.html
https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf
Saturday, May 30, 2015
PRION 2015 ORAL AND POSTER CONGRESSIONAL ABSTRACTS
http://transmissiblespongiformencephalopathy.blogspot.com/2015/05/prion-2015-oral-and-poster.html
Wednesday, December 11, 2013
*** Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease ***
http://creutzfeldt-jakob-disease.blogspot.com/2013/12/detection-of-infectivity-in-blood-of.html
THE BAXTER STUDY...SEE MORE HERE ;
http://tseac.blogspot.com/2009/09/tseac-meeting-february-12-2004-baxter.html
Thursday, November 12, 2015
Evaluation of the protection of primates transfused with variant Creutzfeldt-Jakob disease–infected blood products filtered with prion removal devices: a 5-year update
http://vcjdtransfusion.blogspot.com/2015/11/evaluation-of-protection-of-primates.html
Successful transmission of the chronic wasting disease (CWD) agent to white-tailed deer by intravenous blood transfusion
Author item MAMMADOVA, NAJIBA - Orise Fellow item CASSMANN, ERIC - Orise Fellow item Greenlee, Justin Submitted to: Research in Veterinary Science Publication Type: Peer Reviewed Journal Publication Acceptance Date: 10/14/2020 Publication Date: 12/20/2020 Citation: Mammadova, N., Cassman, E., Greenlee, J.J. 2020. Successful transmission of the chronic wasting disease (CWD) agent to white-tailed deer by intravenous blood transfusion. Research in Veterinary Science. 133:304-306.
Page top 1. Transmission of Bovine Spongiform Encephalopathy (BSE) to Cynomolgus Macaques Reproduces vCJD: Establishment of a non-human Primate Model for vCJD 1.1. BSE, a New Disease in Cattle In 1987, a new prion disease affecting dairy cattle was described in the United Kindom1). Affected cows presented signs of aggressiveness, anxiety, ataxia and were finally found recumbent. The disease was rapidly classified in the group of “transmissible spongiform encephalopathies”, or TSEs, due to the transmissibility of the disease2), as well as the similarities of the neuropathological lesions and molecular hallmark with those found in sheep scrapie and human CJD: neuronal death, spongiform changes, and accumulation of misfolded and aggregated prion protein (termed PrPsc)3). PrPsc is the infectious form of the host prion protein PrP. It is also called a prion (for “proteinaceaous infectious particle4)) or TSE agent. The number of affected cows increased rapidly to top at a 37,280 diagnosed animals in the year of 1992 (OIE data). Thankfully, British epidemiologists recognized that BSE was due to the consumption of prion-tainted meat and bone meal (MBM)5), and the first feed-ban was implemented in 1988, prohibiting the feeding of ruminants with ruminant-derived MBM.
1.2. vCJD in Humans and Transmission of BSE to Non-human Primates In 1991, BSE was reported in a domestic cat that presumably was contaminated via pet food6). Transmission of scrapie from small ruminants to cats had never been described, raising concern that BSE might be more pathogenic than scrapie not only for cats, but also for humans. In order to probe the cow-to-primates species barrier of the BSE agent, we inoculated cynomolgus macaques (Macaca fascicularis) with BSE-infected cow brains at the French Atomic Energy Commision (CEA).
In 1996, 10 young individuals were described in the UK and one in France, harboring an unusual form of CJD that was coined variant CJD (vCJD)7,8). Besides patients being exceptionally young (adolescents and young adults, while sporadic CJD (sCJD) affects people over the age of 60), they exhibited unusual symptoms. Early symptoms were dysaesthesia, behavioral symptoms, depression, ataxia, with myoclonus appearing later on, contrasting with the cognitive course of the disease (memory impairment, dementia) preceding motor impairment, which is most frequently observed in sCJD. Moreover, vCJD patients presented specific neuropathological features with spongiosis and neuronal loss most evident in the basal ganglia and thalamus, and the presence of PrP amyloid plaques (abundant in the cerebral cortex and cerebellum) that were surrounded by vacuoles, giving them a flower-like appearance. These peculiar plaques were called florid plaques7).
At the same time as the first vCJD patients were being described, we were examining the brains of our 3 macaques that had all come down with disease 3 years after intracerebral (IC) inoculation with BSE-infected cow brain. Clinical signs were characterized by behavioral signs such as depression or edginess, as well as truncal ataxia (broad-based gait, tremors) and myoclonus. Neuropathological examination of the brains of the BSE-macaques revealed the presence of florid plaques and other neuropathological features similar to those observed in vCJD patients (Fig. 1). Florid plaques were not present in the brains of macaques inoculated with Kuru or sCJD, and thus were considered specific for infection by the BSE prion. Moreover, PrPsc in BSE-infected macaques and vCJD patients exhibited a similar electrophoretic pattern by western blot (Fig. 1).
In summary, macaques infected by BSE reproduced the behavioral and motor symptoms, the neuropathology and the biochemical signature of vCJD in humans. This study provided the first experimental evidence supporting that vCJD was due to human infection by the BSE agent9), and an experimental model to study the new disease.
1.3. Determination of the Minimal Infectious BSE Dose in Non-human Primates
In a concerted European effort involving 5 laboratories including ours, the BSE-macaque model was then used to evaluate the minimal amount of BSE-infected material necessary to induce vCJD in primates. Results so far show that 5g of infectious BSE cattle brain is sufficient to induce the disease in all recipient animals by the oral route, with 500 mg yielding an incomplete attack rate10,11). The ID50 of BSE cattle brain is 200 mg for cattle12). These results suggest a low species barrier between cattle and non-human primates.
1.4. Adaptation of the BSE Agent to Non-human Primates: Consequences for Human Health
The macaque BSE model provided an opportunity to evaluate the possible risk for humans of secondary inter-human transmission of the BSE/vCJD prion. Accidental human-to-human transmissions of sCJD, resulting in iatrogenic CJD (iCJD) has occurred in several unfortunate circumstances (described in ref.13). One of them was the infection of children with CJD-contaminated human growth hormone (hGH) extracted from cadaveric hypophyses. These iCJD patients had been treated for short stature by injection of hGH in childhood, and 226 of them died of iCJD as young adults, mainly in France and the USA13). Other dramatic iCJD cases had been linked to the surgical implantation of dura-mater grafts, resulting in 228 deaths13). A few cases were also due to corneal grafts and intracranial electrodes. Although all known iCJD cases prior to 2004 had been linked to contamination with central nervous system (CNS) tissue, the possibility existed that the BSE agent would harbor a different distribution in primates than the sCJD agent, thus representing a higher risk of transmission via organ/tissue grafts, contamination of surgical instruments or even blood transfusion.
As a first step for risk assessment, we transmitted the BSE prion from macaque to macaque via different routes. We also established a dose-response (incubation time) for the IC route to provide a baseline for subsequent infectivity measurement studies. This experiment showed that the BSE agent adapts rapidly to primates, as incubation periods shortened from 3 to 1.5 years upon secondary passage at the highest dose14). It also showed that, for a given amount of BSE material (40 mg BSE brain homogenate), the incubation period was the same whether inoculation was done by the IC or the intravenous (IV) route.
2. The Cynomolgus Macaque as a model to Understand the Pathogenesis of Variant Creutzfeldt-Jakob Disease (vCJD) and Model Risk of Interhuman Transmission
2. 1. Distribution of Prions in Tissues and Organs of BSE/vCJD Macaques after Oral or Intravenous (IV) Inoculation
We compared second passage macaques inoculated with BSE prions by the oral or IV routes15). PrPsc was detected by immunohistochemistry and by ELISA after “scrapie associated fibril” (SAF) purification15). In addition to the brain, we detected PrPsc in spleen, tonsils, intestine and sciatic nerve in amounts that did not depend on the inoculation route, with the exceptions of the spleen where PrPsc amounts were up to 4% the amounts found in the brain after IV inoculation, and up to 0.2% those of the brain after oral dosing15).
2. 2. Distribution of Prions in Tissues and Organs of vCJD, Sporadic and Iatrogenic CJD Infected Macaques
We also infected macaques with vCJD, sCJD, iCJD16). As determined earlier, BSE and vCJD prions correspond to the same prion strain, and one or the other denomination is used depending on the species of origin for the brain tissue used as inoculum. All prion strains were inoculated in the same manner (intracerebral and intratonsillar combined), in order to be able to directly compare tissue distribution of PrPsc between strains.
Disease-associated PrP deposits were detected by immunocytochemistry in various organs. They were found in the Peyer’s patches of the gut and other lymphoreticular system (LRS) tissue of BSE/vCJD infected animals (Fig. 2). By PET-blot, we showed that these deposits corresponded to proteinase K-resistant PrP, a biochemical subset of PrPsc. Interestingly, not all Peyer’s patches of a single animal were PrPsc positive (Fig. 2), showing that PrPsc-negative LRS tissue biopsies may lead to false negative diagnostic results.
Pathological PrP deposits were also detected in the enteric nervous system in macaques infected with all prion strains. Fig. 3 shows the localization of pathological PrP in the pericarya of neurons of the myenteric plexus, as well as in small nerve fibers of the inner muscular layer of the intestine.
Pathological PrP deposits were also found in peripheral nerves and in muscle for all CJD strains (Table 1). In the peripheral nerves, they were found mostly at the surface of Schwann cells (Fig. 4). In muscle, they were localized to specific foci in the vicinity of nerve fibers (Fig. 5). Our results suggest that the heterogeneous, patchy distribution of pathological PrP deposits in muscles corresponds to the distribution zones of motor end plates. This study provides a possible explanation for the variably positive detection of pathological PrP in muscle samples of sCJD patients17).
PrPsc amounts were also measured semi-quantitatively using a sensitive biochemical detection method including phosphotungstic acid precipitation as a concentration method, and western blot or ELISA detection16). This method revealed the presence of PrPsc in the spleen of the sCJD infected macaque and tonsils of the iCJD infected macaque, but no PrPsc could be detected in lymph nodes and Peyer’s patches of these animals, a result most likely due to the presence of PrPsc amounts at the threshold of detection in the LRS of sCJD and iCJD macaques, and sampling variations. These results are summarized in Table 1.
In summary, PrPsc was detectable at high levels in organs and tissues of the LRS only in BSE/vCJD infected animals (0.1% to 10% of the amounts found in the brains of the same animals). We interpreted these results as the BSE prion being highly lymphotropic in primates. These findings correlated indeed with the tonsils, spleens and appendices of vCJD patients being found positive for PrPsc18,19,20). We therefore proposed that LRS tissues be considered ‘high-risk’ in vCJD patients only.
However, lower amounts of PrPsc were detected in adrenals, muscles and intestinal tissue of macaques infected with BSE/vCJD as well as sCJD and iCJD, associated with peripheral nerves. Levels were less than 10,000 times lower than brain PrPres levels (<0.001%). We therefore proposed that these tissues be considered “low-risk” for all CJD patients.
Our results expanded upon observations made in vCJD patients that PrPsc is detectable in tonsils, emphasizing that BSE prions are largely lymphotropic in primates, and may replicate in lymph notes, tonsils, spleen and Peyer’s patches before the symptomatic phase. Our subsequent studies confirmed that lymph node biopsies of BSE-inoculated macaques were positive for PrPsc prior to the onset of clinical signs (see below). In another study, gut-associated lymphoid tissue and gut-draining lymph nodes were found positive for PrPsc within one year of oral infection of macaques with cattle BSE21). On the other hand, distribution of PrPsc in muscle of macaques inoculated with vCJD, sCJD and iCJD suggests a centrifugal spread of prions from the CNS to muscle motor plates via motor nerves, occurring after CNS invasion by prions. In addition, it is probable that centripetal spread of prions via peripheral nerves also occurs in earlier stages of infection stochastically from various points of entry, even in the absence of prior LRS replication. We demonstrated this paradigm earlier in severely immunodeficient (SCID) mice infected with mouse-adapted scrapie22). Moreover, spread from the gut to the CNS via autonomic nerve fibers has been shown in experimental scrapie and BSE23,24,25). Fig. 6 illustrates the distribution and proposed propagation of prions in our non-human primate model.
2.2. Blood Infectivity Studies in the Macaque vCJD Model The lymphotropic properties of BSE prions raised the important question of the presence of infectivity in blood of vCJD patients.
We initiated a large blood transfusion study where whole blood, white blood cells or plasma from either vCJD patients or BSE/vCJD macaques was injected by IV or IC to recipient macaques. This experiment led to most macaques surviving over prolonged periods of time (>10 years), and few coming down with BSE/vCJD or intercurrent illnesses. These studies continued after the author of this manuscript left the CEA. Interim transmission results are shown in Fig. 7, and some important observations were as follows. Blood depleted for red blood cells (RBC) from a vCJD patient (7.5 mL) injected intravenously did not result in any clinical disease in the recipient macaque after 10 years, yet this animal harbored positive IHC staining in the inguinal lymph nodes (LNs). Another macaque, who had received 25 mL of RBC-depleted blood intravenously from another vCJD patient, died suddenly at 42 months after inoculation, and harbored PrPsc positive inguinal LNs. Two other animals, that received 500 µL of buffy coat (BC) from vCJD patients by IC, were still alive 10 years after inoculation (with PrPsc positive LNs, Fig. 7A). A whole blood transfusion of 40 mL from a vCJD macaque (who died 3 years after intracerebral + intratonsillar inoculation of human vCJD brain homogenate) induced clinical signs of vCJD in the recipient macaque 66 months after the transfusion. Inguinal lymph nodes biopsies had been positive since 45 months, i.e. 75% of the incubation period (Fig. 7B). Other macaques transfused with blood from BSE-macaques survived more than 10 years, but some had positive LNs (Fig. 7C). Another notable result was the transmission of BSE infection by the plasma from a macaque that had been dosed orally with cattle BSE 27.5 months earlier. The donor macaque died with a behavioral syndrome of self-injury 117 months after challenge with a diagnosis of probable BSE, hence infectivity was present in its blood at a quarter of the incubation period (Fig. 7D).
In 2004, the first transfusion-related case of vCJD was described in a patient who had been transfused with non-leucoreduced red blood cells from a donor who developed vCJD 3.5 years after the donation26). A total of four transfusion-related vCJD transmissions have been reported to date27).
Acknowledgments
I thank the many people who supported and participated in this work at the CEA: Dominique Dormont, Jean-Philippe Deslys, Christian Herzog, Nathalie Lescoutra, Nicole Salès, Emmanuel Comoy, René Rioux. I also thank Ray Bradley and Michael Dawson for providing BSE-infected cattle brain homogenates. I am thankful to Robert Will and Nicolas Kopp for providing vCJD samples, and to James Ironside for his collaboration on the neuropathology of BSE-infected macaques. I am grateful to my European collaborators Maurizio Pocchiari, Gerhard Hunsmann, Johannes Löwer, Pär Bierke, Loredana Ingrosso, Uwe Hahmann, Dirk Motzkus, Edgar Holznagel, for their friendship and for embarking on this challenging project.
https://www.jstage.jst.go.jp/article/foodsafetyfscj/5/1/5_2016034/_html
https://www.jstage.jst.go.jp/article/foodsafetyfscj/5/1/5_2016034/_pdf
Volume 23, Number 6—June 2017 Synopsis
Sporadic Creutzfeldt-Jakob Disease in 2 Plasma Product Recipients, United Kingdom, P. Urwin et al.
View Summary
Two cases of sporadic CJD with clotting disorders have been identified, but this may represent a chance event.
https://wwwnc.cdc.gov/eid/ahead-of-print
Volume 23, Number 6—June 2017
Research
Distribution and Quantitative Estimates of Variant Creutzfeldt-Jakob Disease Prions in Tissues of Clinical and Asymptomatic Patients
Jean Y. Douet, Caroline Lacroux, Naima Aron, Mark W. Head, Séverine Lugan, Cécile Tillier, Alvina Huor, Hervé Cassard, Mark Arnold, Vincent Beringue, James W. Ironside, and Olivier Andréoletti
Comments to Author Author affiliations: Institut National de la Recherche Agronomique, Toulouse, France (J.Y. Douet, C. Lacroux, N. Aron, S. Lugan, C. Tillier, A. Huor, H. Cassard, O. Andréoletti); University of Edinburgh, Edinburgh, Scotland, UK (M.W. Head, J.W. Ironside); Animal and Plant Health Agency, Loughborough, UK (M. Arnold); Institut National de la Recherche Agronomique, Jouy-en-Josas, France (V. Beringue) Suggested citation for this article
Abstract
In the United-Kingdom, ≈1 of 2,000 persons could be infected with variant Creutzfeldt-Jakob disease (vCJD). Therefore, risk of transmission of vCJD by medical procedures remains a major concern for public health authorities. In this study, we used in vitro amplification of prions by protein misfolding cyclic amplification (PMCA) to estimate distribution and level of the vCJD agent in 21 tissues from 4 patients who died of clinical vCJD and from 1 asymptomatic person with vCJD. PMCA identified major levels of vCJD prions in a range of tissues, including liver, salivary gland, kidney, lung, and bone marrow. Bioassays confirmed that the quantitative estimate of levels of vCJD prion accumulation provided by PMCA are indicative of vCJD infectivity levels in tissues. Findings provide critical data for the design of measures to minimize risk for iatrogenic transmission of vCJD.
snip...
Discussion
Most previous studies with tissue from vCJD patients have failed to identify consistent accumulation of the vCJD agent outside the nervous and lymphoreticular systems. However, data obtained in this study clearly demonstrate the presence of vCJD prions in a wide and unexpected variety of peripheral tissues.
Natural scrapie and experimental BSE in sheep are 2 models of orally transmitted prion diseases (24,25). In both diseases, the agent accumulates in the lymphoreticular system and the enteric nervous system during the early preclinical phase of the incubation period. Moreover, an early and persistent prionemia is observed in asymptomatic infected animals (26,27). These features were also observed in vCJD in humans and in view of the likely origin of vCJD (oral exposure to BSE agent), these similarities have led to a consensus that BSE and scrapie in sheep and vCJD in human have a common pathogenesis (28).
Although vCJD prions in a variety tissues, such as bone marrow, kidney, salivary gland, skeletal muscle, pancreas, liver, or heart, might be surprising, each of these tissue has already been demonstrated to accumulate prion infectivity or abnormal prion protein in TSE-infected sheep (29–33). Because low levels of infectivity have been reported in blood fractions from a vCJD-affected patient, such widespread tissue positivity might be derived from residual blood, rather than from the solid tissue in these samples (16). However, this proposal seems unlikely because in whole blood PMCA amplification inhibitors preclude detection of endogenous vCJD agent by this method (11,34–36).
The patient in our study who was infected with a prion containing PRNP gene codon 129 Met/Val is 1 of only 2 identified vCJD agent–infected persons known to have died of other causes before onset clinical symptoms of vCJD, and the only person who provided consent to sample autopsy tissues for research. For this patient, all previous investigations did not detect abnormal prion protein or infectivity in the brain (12,37). The negative PMCA results we obtained for cerebral cortex, dorsal root ganglia, and trigeminal ganglia tissue from this patient are consistent with a lack of central nervous system involvement at the time of death. However, PMCA seeding activity in the pituitary gland was surprising in this instance.
The presence of abnormal prion protein accumulation in the pituitary gland and other circumventricular organs before deposition of PrPres in surrounding brain has been reported in TSE-infected sheep (38). However, this phenomenon in animals does not represent the main route for neuroinvasion and is a probable consequence of hematogenous dissemination of the TSE agent through the fenestrated capillary system of the circumventricular organs, which is substantially more permeable than the other capillaries in the brain (blood–brain barrier). Therefore, this finding might be a consequence of the hematogenous route of secondary vCJD in this person (by transfusion of packed erythrocytes from a vCJD-infected donor), in contrast to the oral route of infection in primary clinical vCJD cases (12).
vCJD prions were detected in certain peripheral tissues from the patients infected with a prion containing the PRNP gene codon 129 Met/Val. Although distribution of vCJD seeding activity in lymphoreticular tissues was similar to that observed for symptomatic vCJD patients, several tissues that were positive in clinically affected patients were negative in this heterozygous asymptomatic person. These findings suggest that involvement of some peripheral tissues might occur at a later stage in the incubation period than others, or that they could involve recirculation of the agent from the central nervous system (i.e., centrifugal spread in a late state). However, we cannot discount the possibility that that these differences in tissue distribution are caused by the hematogenous route of infection in this person (as opposed to the probable oral route in patients with clinical vCJD) or the difference between the PRNP gene codon 129 genotype of the asymptomatic vCJD–affected person (PRNP gene codon 129 Met/Val) and persons with clinical vCJD (PRNP gene codon 129 Met/Met).
Irrespective of the actual explanation for these differences, the presence of vCJD agent in peripheral tissues of patients during preclinical and clinical stage of the disease indicates the potential for iatrogenic transmission of this fatal neurologic condition by surgical procedures. Furthermore, this finding shows that, for certain peripheral tissues, a level of infectivity equivalent to an end stage titer (and attendant risk) is reached at a preclinical stage.
Several hundred cases of iatrogenic CJD have been reported worldwide. These cases appear to result from transmission of sporadic CJD, and most cases have occurred in recipients of human dura mater grafts or after administration of human growth hormone extracted from cadaveric pituitaries (39). Although in sporadic CJD the distribution of the agent is largely restricted to the nervous system (central and peripheral), the wide distribution of the vCJD agent in the asymptomatic infected patient we report might serve to increase the range of medical procedures, including dentistry, organ transplant, and surgery involving nondisposable equipment, that might result in iatrogenic transmission of vCJD (40–43).
Nevertheless, >20 years after identification of the first vCJD patients, only 5 cases that are a probable consequence of iatrogenic vCJD transmission are known, all in the United Kingdom and associated with blood and blood products. These cases were caused by transfusion of non–leukocyte-depleted erythrocyte concentrates or by treatment involving large amounts of pooled plasma from the United Kingdom that were known to include donations from persons who later showed development of vCJD (12,44–46).
None of the 220 other vCJD cases identified worldwide have been linked to any other medical or dental procedure. Whereas this fact is reassuring, it would be unwise to disregard the threat that vCJD still poses for public health. Despite the relatively low number (n = 178) of vCJD clinical cases observed in the United Kingdom, the most recent epidemiologic studies indicate that ≈1 of 2,000 persons in the United Kingdom could be infected with the vCJD agent (as indicated by the presence of abnormal prion protein detected by immunohistochemical analysis of lymphoid follicles in the appendix). Each asymptomatic vCJD-infected person represents a potential source of secondary infection. The data in our report offer an opportunity for refining measures that were implemented in many countries to limit the risk for vCJD iatrogenic transmission. The apparent concordance between PMCA biochemical and infectivity bioassay data, and the higher analytical sensitivity of PMCA, suggest that future research need not rely exclusively on time-consuming and costly animal bioassay.
Our results indicate the need for vCJD screening assays. After more than a decade of effort, several vCJD blood detection tests have reached a stage in their development that could enable their evaluation as screening or confirmatory assays (11,47,48). In particular, there is now a strong case for use of PMCA in a highly sensitive and specific blood test for vCJD, as indicated by our previous studies (11,16) and studies by Bougard et al. (35) and Concha-Marambio et al. (36). The relationship shown here between PrPres amplification by PMCA and detection of infectivity by bioassay indicates that PMCA seeding activity is a good surrogate marker of infectivity and could provide a sound basis for a vCJD blood test for use with blood or tissue donors.
Dr. Douet is a research scientist and assistant lecturer in ophthalmology at the National Veterinary School of Toulouse, Toulouse, France. His primary research interests are the pathogenesis of the prion disease with special emphasis on the iatrogenic risk of transmission.
Acknowledgment
This study was supported in part by the Department of Health Policy Research Programme and the Scottish Government. The National CJD Research and Surveillance Unit is supported by the Policy Research Program of the Department of Health and the Scottish Government (DH121/5061). The Edinburgh Brain Bank is supported by the Medical Research Council (MRC grant G0900580). The Unité Mixte de Recherche 1225, Ecole Nationale Vétérinaire de Toulouse was supported by the European Union FEDER/INTERREG (EFA282/13 TRANSPRION), the Institut National de la Recherche Agronomique Institut Carnot en Santé Animale, and an Agence Nationale Recherche grant (Unmasking Blood Prions; ANR-15-CE18-0028).
https://wwwnc.cdc.gov/eid/article/23/6/16-1734_article
MONDAY, NOVEMBER 23, 2015
Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study ORIGINAL RESEARCH
Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study
Diane L. Ritchie1,*, Susan V. Gibson2,†, Christian R. Abee3, Thomas R. Kreil4, James W. Ironside1 and Paul Brown5
Article first published online: 23 NOV 2015
DOI: 10.1111/trf.13422
© 2015 AABB
Issue
Cover image for Vol. 55 Issue 11
Transfusion
Early View (Online Version of Record published before inclusion in an issue)
Abstract
BACKGROUND
Four secondary transmissions of variant Creutzfeldt-Jakob disease (vCJD) infectivity have been associated with the transfusion of nonleukoreduced red blood cells collected from vCJD patients during the asymptomatic phase of the disease. Establishing efficient experimental models for assessing the risk of future transmissions of vCJD infectivity via blood transfusion is of paramount importance in view of a study of archived appendix samples in which the prevalence of asymptomatic vCJD infection in the United Kingdom was estimated at approximately 1 in 2000 of the population. In this study, we investigated transmission of vCJD and sporadic CJD (sCJD) infectivity from blood using the squirrel monkey, which is highly susceptible to experimental challenge with human prion disease.
STUDY DESIGN AND METHODS
Whole blood collected from vCJD- and sCJD-infected squirrel monkeys was transfused at multiple time points into recipient squirrel monkeys. Blood recipients were euthanized approximately 7 years after their first blood transfusion.
RESULTS
No clinical or pathologic signs of a prion disease were observed in either the sCJD- or the vCJD-transfused monkeys, and immunohistochemistry and biochemical investigations showed no PrPTSE in central nervous system or lymphoreticular tissues. Similarly, monkeys inoculated intracerebrally (IC) and intravenously (IV) with either buffy coat or plasma from vCJD and sCJD patients failed to develop disease. However, white blood cells from a chimpanzee-passaged strain of human Gerstmann-Sträussler-Scheinker (GSS) disease transmitted autopsy-proven disease to two IC-inoculated monkeys after incubation periods of 34 and 39 months.
CONCLUSION
Blood transmits GSS but not sCJD or vCJD infectivity to IC- or IV-inoculated squirrel monkeys within a 7-year observation period.
http://onlinelibrary.wiley.com/doi/10.1111/trf.13422/abstract
2015 PRION CONFERENCE
*** RE-P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study
***suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. ***
P.164: Blood transmission of prion infectivity in the squirrel monkey: The Baxter study
Paul Brown1, Diane Ritchie2, James Ironside2, Christian Abee3, Thomas Kreil4, and Susan Gibson5 1NIH (retired); Bethesda, MD USA; 2University of Edinburgh; Edinburgh, UK; 3University of Texas; Bastrop, TX USA; 4Baxter Bioscience; Vienna, Austria; 5University of South Alabama; Mobile, AL USA
Five vCJD disease transmissions and an estimated 1 in 2000 ‘silent’ infections in UK residents emphasize the continued need for information about disease risk in humans. A large study of blood component infectivity in a non-human primate model has now been completed and analyzed. Among 1 GSS, 4 sCJD, and 3 vCJD cases, only GSS leukocytes transmitted disease within a 5–6 year surveillance period. A transmission study in recipients of multiple whole blood transfusions during the incubation and clinical stages of sCJD and vCJD in ic-infected donor animals was uniformly negative. These results, together with other laboratory studies in rodents and nonhuman primates and epidemiological observations in humans, suggest that blood donations from cases of GSS (and perhaps other familial forms of TSE) carry more risk than from vCJD cases, and that little or no risk is associated with sCJD. The issue of decades-long incubation periods in ‘silent’ vCJD carriers remains open.
https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf
ran across an old paper from 1984 ;
***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent. ***
http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html
From: Terry S. Singeltary Sr.
Sent: Saturday, November 15, 2014 9:29 PM
To: Terry S. Singeltary Sr.
Subject: THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL 1984
THE EPIDEMIOLOGY OF CREUTZFELDT-JAKOB DISEASE R. G. WILL
1984
snip...
http://web.archive.org/web/20050425210551/http://www.bseinquiry.gov.uk/files/mb/m26/tab01.pdf
THE BAXTER STUDY...SEE MORE HERE ;
http://tseac.blogspot.com/2009/09/tseac-meeting-february-12-2004-baxter.html
https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf
Saturday, May 30, 2015
PRION 2015 ORAL AND POSTER CONGRESSIONAL ABSTRACTS
http://transmissiblespongiformencephalopathy.blogspot.com/2015/05/prion-2015-oral-and-poster.html
Wednesday, December 11, 2013
*** Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease ***
http://creutzfeldt-jakob-disease.blogspot.com/2013/12/detection-of-infectivity-in-blood-of.html
THE BAXTER STUDY...SEE MORE HERE ;
http://tseac.blogspot.com/2009/09/tseac-meeting-february-12-2004-baxter.html
Thursday, November 12, 2015
Evaluation of the protection of primates transfused with variant Creutzfeldt-Jakob disease–infected blood products filtered with prion removal devices: a 5-year update
http://vcjdtransfusion.blogspot.com/2015/11/evaluation-of-protection-of-primates.html
Successful transmission of the chronic wasting disease (CWD) agent to white-tailed deer by intravenous blood transfusion
Author item MAMMADOVA, NAJIBA - Orise Fellow item CASSMANN, ERIC - Orise Fellow item Greenlee, Justin Submitted to: Research in Veterinary Science Publication Type: Peer Reviewed Journal Publication Acceptance Date: 10/14/2020 Publication Date: 12/20/2020 Citation: Mammadova, N., Cassman, E., Greenlee, J.J. 2020. Successful transmission of the chronic wasting disease (CWD) agent to white-tailed deer by intravenous blood transfusion. Research in Veterinary Science. 133:304-306.
https://doi.org/10.1016/j.rvsc.2020.10.009. DOI: https://doi.org/10.1016/j.rvsc.2020.10.009
Interpretive Summary: Chronic wasting disease (CWD) is a fatal disease of cervids that causes damaging changes in the brain. The infectious agent is an abnormal protein called a prion that has misfolded from its normal state. Chronic wasting disease may be transmitted from ingestion of prions shed in bodily fluids (e.g. feces, urine, saliva, placenta tissue) of infected animals. Few studies have also reported detection of infectious prions in blood. To determine if CWD-infected blood can transmit prion disease, recipient deer were inoculated intravenously (IV) with blood derived from a CWD-infected white-tailed deer. We found that two out of three animals developed disease. This study complements and supports an earlier finding that CWD can be transmitted to deer by intravenous blood transfusion from white-tailed deer with CWD. This information is useful to wildlife and agricultural officials that are involved in efforts to control the spread of chronic wasting disease.
Technical Abstract: Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSEs) that affects free-ranging and captive cervid species. The infectious agent of CWD may be transmitted from ingestion of prions shed in bodily fluids (e.g. feces, urine, saliva, placenta tissue) of infected animals, contaminated pastures, and/or decomposing carcasses from dead animals. Studies have also demonstrated prion infectivity in whole blood or blood fractions of CWD infected animals. To determine if CWD-infected blood contained sufficient levels of prion infectivity to cause disease, recipient deer were inoculated intravenously (IV) with blood derived from a CWD-infected white-tailed deer. We found that the CWD agent can be successfully transmitted to white-tailed deer by a single intravenous blood transfusion with a mean incubation period of approximately 35 months and an attack rate of 100%. This study complements and supports an earlier finding that CWD can be transmitted to deer by intravenous blood transfusion from white-tailed deer with CWD.
https://www.ars.usda.gov/research/publications/publication/?seqNo115=373622
PLoS One . 2020 Aug 20;15(8):e0237410. doi: 10.1371/journal.pone.0237410. eCollection 2020.
Very low oral exposure to prions of brain or saliva origin can transmit chronic wasting disease
Nathaniel D Denkers 1, Clare E Hoover 2, Kristen A Davenport 3, Davin M Henderson 1, Erin E McNulty 1, Amy V Nalls 1, Candace K Mathiason 1, Edward A Hoover 1 Affiliations expand PMID: 32817706 PMCID: PMC7446902 DOI: 10.1371/journal.pone.0237410 Erratum in Correction: Very low oral exposure to prions of brain or saliva origin can transmit chronic wasting disease. PLOS ONE Staff. PLoS One. 2021 Jun 10;16(6):e0253356. doi: 10.1371/journal.pone.0253356. eCollection 2021. PMID: 34111230 Free PMC article.
Abstract
The minimum infectious dose required to induce CWD infection in cervids remains unknown, as does whether peripherally shed prions and/or multiple low dose exposures are important factors in CWD transmission. With the goal of better understand CWD infection in nature, we studied oral exposures of deer to very low doses of CWD prions and also examined whether the frequency of exposure or prion source may influence infection and pathogenesis. We orally inoculated white-tailed deer with either single or multiple divided doses of prions of brain or saliva origin and monitored infection by serial longitudinal tissue biopsies spanning over two years. We report that oral exposure to as little as 300 nanograms (ng) of CWD-positive brain or to saliva containing seeding activity equivalent to 300 ng of CWD-positive brain, were sufficient to transmit CWD disease. This was true whether the inoculum was administered as a single bolus or divided as three weekly 100 ng exposures. However, when the 300 ng total dose was apportioned as 10, 30 ng doses delivered over 12 weeks, no infection occurred. While low-dose exposures to prions of brain or saliva origin prolonged the time from inoculation to first detection of infection, once infection was established, we observed no differences in disease pathogenesis. These studies suggest that the CWD minimum infectious dose approximates 100 to 300 ng CWD-positive brain (or saliva equivalent), and that CWD infection appears to conform more with a threshold than a cumulative dose dynamic.
snip...
In conclusion, we have attempted to model and better understand CWD infection relative to natural exposure. The results demonstrate: (a) that the minimum CWD oral infectious dose is vastly lower than historical studies used to establish infection; (b) that a direct relationship exists between dose and incubation time to first prion replication detection in tonsils, irrespective of genotype; (c) that a difference was not discernible between brain vs. saliva source prions in ability to establish infection or in resultant disease course; and (d) that the CWD infection process appears to conform more to a threshold dose than an accumulative dose dynamic.
https://pubmed.ncbi.nlm.nih.gov/32817706/
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237410
JAMA. 2001;285(6):733-734. doi:10-1001/pubs.JAMA-ISSN-0098-7484-285-6-jlt0214
February 14, 2001
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Terry S. Singeltary, Sr
Author Affiliations
JAMA. 2001;285(6):733-734. doi:10-1001/pubs.JAMA-ISSN-0098-7484-285-6-jlt0214
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
https://jamanetwork.com/journals/jama/article-abstract/1031186
Prion Scientific Advisors and Consultants Staff Meeting Singeltary Submission Freas Monday, January 08,2001 3:03 PM
Scientific Advisors and Consultants Staff 2001 Advisory Committee TSE PRION Singeltary Submission Freas Monday, January 08,2001 3:03 PM
FDA Singeltary submission 2001
Greetings again Dr. Freas and Committee Members,
I wish to submit the following information to the Scientific Advisors and Consultants Staff 2001 Advisory Committee (short version). I understand the reason of having to shorten my submission, but only hope that you add it to a copy of the long version, for members to take and read at their pleasure, (if cost is problem, bill me, address below). So when they realize some time in the near future of the 'real' risks i speak of from human/animal TSEs and blood/surgical products. I cannot explain the 'real' risk of this in 5 or 10 minutes at some meeting, or on 2 or 3 pages, but will attempt here: fda link is dead in the water;
http://web.archive.org/web/20041212232925/http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
https://tseac.blogspot.com/2009/05/meeting-of-transmissible-spongiform.html
26 MARCH 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Terry S. Singeltary, retired (medically)
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?
https://www.neurology.org/doi/10.1212/01.WNL.0000036913.87823.D6
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009 Plos Singeltary August 10, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
August 10, 2009
Greetings,
I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. North America seems to have the most species with documented Transmissible Spongiform Encephalopathy's, most all of which have been rendered and fed back to food producing animals and to humans for years. If you look at the statistics, sporadic CJD seems to be rising in the USA, and has been, with atypical cases of the sCJD. I find deeply disturbing in the year of 2009, that Human Transmissible Spongiform Encephalopathy of any strain and or phenotype, of all age groups, and I stress all age groups, because human TSE's do not know age, and they do not know borders. someone 56 years old, that has a human TSE, that has surgery, can pass this TSE agent on i.e. friendly fire, and or passing it forward, and there have been documented nvCJD in a 74 year old. Remembering also that only sporadic CJD has been documented to transmit via iatrogenic routes, until recently with the 4 cases of blood related transmission, of which the origin is thought to be nvCJD donors. However most Iatrogenic CJD cases are nothing more than sporadic CJD, until the source is proven, then it becomes Iatrogenic. An oxymoron of sorts, because all sporadic CJD is, are multiple forms, or strains, or phenotypes of Creutzfeldt Jakob Disease, that the route and source and species have not been confirmed and or documented. When will the myth of the UKBSEnvCJD only theory be put to bed for good. This theory in my opinion, and the following there from, as the GOLD STANDARD, has done nothing more than help spread this agent around the globe. Politics and money have caused the terrible consequences to date, and the fact that TSEs are a slow incubating death, but a death that is 100% certain for those that are exposed and live long enough to go clinical. once clinical, there is no recourse, to date.
But, while sub-clinical, how many can one exposed human infect?
Can humans exposed to CWD and scrapie strains pass it forward as some form of sporadic CJD in the surgical and medical arenas?
why must we wait decades and decades to prove this point, only to expose millions needlessly, only for the sake of the industries involved?
would it not have been prudent from the beginning to just include all TSE's, and rule them out from there with transmission studies and change policies there from, as opposed to doing just the opposite?
The science of TSE's have been nothing more than a political circus since the beginning, and for anyone to still believe in this one strain, one group of bovines, in one geographical location, with only one age group of human TSE i.e. nvCJD myth, for anyone to believe this today only enhances to spreading of these human and animal TSE's. This is exactly why we have been in this quagmire.
The ones that believe that there is a spontaneous CJD in 85%+ of all cases of human TSE, and the ones that do not believe that cattle can have this same phenomenon, are two of the same, the industry, and so goes the political science aspect of this tobacco and or asbestos scenario i.e. follow the money. I could go into all angles of this man made nightmare, the real facts and science, for instance, the continuing rendering technology and slow cooking with low temps that brewed this stew up, and the fact that THE USA HAD THIS TECHNOLOGY FIRST AND SHIPPED IT TO THE U.K. SOME 5 YEARS BEFORE THE U.S. STARTED USING THE SAME TECHNOLOGY, to save on fuel cost. This is what supposedly amplified the TSE agent via sheep scrapie, and spread via feed in the U.K. bovine, and other countries exporting the tainted product. BUT most everyone ignores this fact, and the fact that the U.S. has been recycling more TSE, from more species with TSEs, than any other country documented, but yet, it's all spontaneous, and the rise in sporadic CJD in the U.S. is a happenstance of bad luck ??? I respectfully disagree. To top that all off, the infamous BSE-FIREWALL that the USDA always brags about was nothing more than ink on paper, and I can prove this. YOU can ignore it, but this is FACT (see source, as late as 2007, in one recall alone, some 10,000,000 MILLION POUNDS OF BANNED MAD COW FEED WENT OUT INTO COMMERCE TO BE FED OUT, and most was never recovered. This was banned blood laced, meat and bone meal. 2006 was a banner year for banned mad cow protein going into commerce in the U.S. (see source of FDA feed ban warning letter below). I stress that the August 4, 1997 USA mad cow feed ban and this infamous BSE firewall, was nothing more than ink on paper, it was never enforceable.
I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route. This would further have to be broken down to strain of species and then the route of transmission would further have to be broken down. Accumulation and Transmission are key to the threshold from sub- clinical to clinical disease, and key to all this, is to stop the amplification and transmission of this agent, the spreading of, no matter what strain. In my opinion, to continue with this myth that the U.K. strain of BSE one strain TSE in cows, and the nv/v CJD one strain TSE humans, and the one geographical location source i.e. U.K., and that all the rest of human TSE are just one single strain i.e. sporadic CJD, a happenstance of bad luck that just happens due to a twisted protein that just twisted the wrong way, IN 85%+ OF ALL HUMAN TSEs, when to date there are 6 different phenotypes of sCJD, and growing per Gambetti et al, and that no other animal TSE transmits to humans ??? With all due respect to all Scientist that believe this, I beg to differ. To continue with this masquerade will only continue to spread, expose, and kill, who knows how many more in the years and decades to come. ONE was enough for me, My Mom, hvCJD i.e. Heidenhain Variant CJD, DOD 12/14/97 confirmed, which is nothing more than another mans name added to CJD, like CJD itself, Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker syndrome, just another CJD or human TSE, named after another human. WE are only kidding ourselves with the current diagnostic criteria for human and animal TSE, especially differentiating between the nvCJD vs the sporadic CJD strains and then the GSS strains and also the FFI fatal familial insomnia strains or the ones that mimics one or the other of those TSE? Tissue infectivity and strain typing of the many variants of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously. ...
please see history, and the ever evolving TSE science to date ;
Saturday, June 13, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/04ce2b24-613d-46e6-9802-4131e2bfa6fd
https://web.archive.org/web/20210421175119/https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/04ce2b24-613d-46e6-9802-4131e2bfa6fd
Technical Abstract: Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSEs) that affects free-ranging and captive cervid species. The infectious agent of CWD may be transmitted from ingestion of prions shed in bodily fluids (e.g. feces, urine, saliva, placenta tissue) of infected animals, contaminated pastures, and/or decomposing carcasses from dead animals. Studies have also demonstrated prion infectivity in whole blood or blood fractions of CWD infected animals. To determine if CWD-infected blood contained sufficient levels of prion infectivity to cause disease, recipient deer were inoculated intravenously (IV) with blood derived from a CWD-infected white-tailed deer. We found that the CWD agent can be successfully transmitted to white-tailed deer by a single intravenous blood transfusion with a mean incubation period of approximately 35 months and an attack rate of 100%. This study complements and supports an earlier finding that CWD can be transmitted to deer by intravenous blood transfusion from white-tailed deer with CWD.
https://www.ars.usda.gov/research/publications/publication/?seqNo115=373622
PLoS One . 2020 Aug 20;15(8):e0237410. doi: 10.1371/journal.pone.0237410. eCollection 2020.
Very low oral exposure to prions of brain or saliva origin can transmit chronic wasting disease
Nathaniel D Denkers 1, Clare E Hoover 2, Kristen A Davenport 3, Davin M Henderson 1, Erin E McNulty 1, Amy V Nalls 1, Candace K Mathiason 1, Edward A Hoover 1 Affiliations expand PMID: 32817706 PMCID: PMC7446902 DOI: 10.1371/journal.pone.0237410 Erratum in Correction: Very low oral exposure to prions of brain or saliva origin can transmit chronic wasting disease. PLOS ONE Staff. PLoS One. 2021 Jun 10;16(6):e0253356. doi: 10.1371/journal.pone.0253356. eCollection 2021. PMID: 34111230 Free PMC article.
Abstract
The minimum infectious dose required to induce CWD infection in cervids remains unknown, as does whether peripherally shed prions and/or multiple low dose exposures are important factors in CWD transmission. With the goal of better understand CWD infection in nature, we studied oral exposures of deer to very low doses of CWD prions and also examined whether the frequency of exposure or prion source may influence infection and pathogenesis. We orally inoculated white-tailed deer with either single or multiple divided doses of prions of brain or saliva origin and monitored infection by serial longitudinal tissue biopsies spanning over two years. We report that oral exposure to as little as 300 nanograms (ng) of CWD-positive brain or to saliva containing seeding activity equivalent to 300 ng of CWD-positive brain, were sufficient to transmit CWD disease. This was true whether the inoculum was administered as a single bolus or divided as three weekly 100 ng exposures. However, when the 300 ng total dose was apportioned as 10, 30 ng doses delivered over 12 weeks, no infection occurred. While low-dose exposures to prions of brain or saliva origin prolonged the time from inoculation to first detection of infection, once infection was established, we observed no differences in disease pathogenesis. These studies suggest that the CWD minimum infectious dose approximates 100 to 300 ng CWD-positive brain (or saliva equivalent), and that CWD infection appears to conform more with a threshold than a cumulative dose dynamic.
snip...
In conclusion, we have attempted to model and better understand CWD infection relative to natural exposure. The results demonstrate: (a) that the minimum CWD oral infectious dose is vastly lower than historical studies used to establish infection; (b) that a direct relationship exists between dose and incubation time to first prion replication detection in tonsils, irrespective of genotype; (c) that a difference was not discernible between brain vs. saliva source prions in ability to establish infection or in resultant disease course; and (d) that the CWD infection process appears to conform more to a threshold dose than an accumulative dose dynamic.
https://pubmed.ncbi.nlm.nih.gov/32817706/
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237410
JAMA. 2001;285(6):733-734. doi:10-1001/pubs.JAMA-ISSN-0098-7484-285-6-jlt0214
February 14, 2001
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Terry S. Singeltary, Sr
Author Affiliations
JAMA. 2001;285(6):733-734. doi:10-1001/pubs.JAMA-ISSN-0098-7484-285-6-jlt0214
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
https://jamanetwork.com/journals/jama/article-abstract/1031186
Prion Scientific Advisors and Consultants Staff Meeting Singeltary Submission Freas Monday, January 08,2001 3:03 PM
Scientific Advisors and Consultants Staff 2001 Advisory Committee TSE PRION Singeltary Submission Freas Monday, January 08,2001 3:03 PM
FDA Singeltary submission 2001
Greetings again Dr. Freas and Committee Members,
I wish to submit the following information to the Scientific Advisors and Consultants Staff 2001 Advisory Committee (short version). I understand the reason of having to shorten my submission, but only hope that you add it to a copy of the long version, for members to take and read at their pleasure, (if cost is problem, bill me, address below). So when they realize some time in the near future of the 'real' risks i speak of from human/animal TSEs and blood/surgical products. I cannot explain the 'real' risk of this in 5 or 10 minutes at some meeting, or on 2 or 3 pages, but will attempt here: fda link is dead in the water;
http://web.archive.org/web/20041212232925/http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
https://tseac.blogspot.com/2009/05/meeting-of-transmissible-spongiform.html
26 MARCH 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Terry S. Singeltary, retired (medically)
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?
https://www.neurology.org/doi/10.1212/01.WNL.0000036913.87823.D6
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009 Plos Singeltary August 10, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
August 10, 2009
Greetings,
I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. North America seems to have the most species with documented Transmissible Spongiform Encephalopathy's, most all of which have been rendered and fed back to food producing animals and to humans for years. If you look at the statistics, sporadic CJD seems to be rising in the USA, and has been, with atypical cases of the sCJD. I find deeply disturbing in the year of 2009, that Human Transmissible Spongiform Encephalopathy of any strain and or phenotype, of all age groups, and I stress all age groups, because human TSE's do not know age, and they do not know borders. someone 56 years old, that has a human TSE, that has surgery, can pass this TSE agent on i.e. friendly fire, and or passing it forward, and there have been documented nvCJD in a 74 year old. Remembering also that only sporadic CJD has been documented to transmit via iatrogenic routes, until recently with the 4 cases of blood related transmission, of which the origin is thought to be nvCJD donors. However most Iatrogenic CJD cases are nothing more than sporadic CJD, until the source is proven, then it becomes Iatrogenic. An oxymoron of sorts, because all sporadic CJD is, are multiple forms, or strains, or phenotypes of Creutzfeldt Jakob Disease, that the route and source and species have not been confirmed and or documented. When will the myth of the UKBSEnvCJD only theory be put to bed for good. This theory in my opinion, and the following there from, as the GOLD STANDARD, has done nothing more than help spread this agent around the globe. Politics and money have caused the terrible consequences to date, and the fact that TSEs are a slow incubating death, but a death that is 100% certain for those that are exposed and live long enough to go clinical. once clinical, there is no recourse, to date.
But, while sub-clinical, how many can one exposed human infect?
Can humans exposed to CWD and scrapie strains pass it forward as some form of sporadic CJD in the surgical and medical arenas?
why must we wait decades and decades to prove this point, only to expose millions needlessly, only for the sake of the industries involved?
would it not have been prudent from the beginning to just include all TSE's, and rule them out from there with transmission studies and change policies there from, as opposed to doing just the opposite?
The science of TSE's have been nothing more than a political circus since the beginning, and for anyone to still believe in this one strain, one group of bovines, in one geographical location, with only one age group of human TSE i.e. nvCJD myth, for anyone to believe this today only enhances to spreading of these human and animal TSE's. This is exactly why we have been in this quagmire.
The ones that believe that there is a spontaneous CJD in 85%+ of all cases of human TSE, and the ones that do not believe that cattle can have this same phenomenon, are two of the same, the industry, and so goes the political science aspect of this tobacco and or asbestos scenario i.e. follow the money. I could go into all angles of this man made nightmare, the real facts and science, for instance, the continuing rendering technology and slow cooking with low temps that brewed this stew up, and the fact that THE USA HAD THIS TECHNOLOGY FIRST AND SHIPPED IT TO THE U.K. SOME 5 YEARS BEFORE THE U.S. STARTED USING THE SAME TECHNOLOGY, to save on fuel cost. This is what supposedly amplified the TSE agent via sheep scrapie, and spread via feed in the U.K. bovine, and other countries exporting the tainted product. BUT most everyone ignores this fact, and the fact that the U.S. has been recycling more TSE, from more species with TSEs, than any other country documented, but yet, it's all spontaneous, and the rise in sporadic CJD in the U.S. is a happenstance of bad luck ??? I respectfully disagree. To top that all off, the infamous BSE-FIREWALL that the USDA always brags about was nothing more than ink on paper, and I can prove this. YOU can ignore it, but this is FACT (see source, as late as 2007, in one recall alone, some 10,000,000 MILLION POUNDS OF BANNED MAD COW FEED WENT OUT INTO COMMERCE TO BE FED OUT, and most was never recovered. This was banned blood laced, meat and bone meal. 2006 was a banner year for banned mad cow protein going into commerce in the U.S. (see source of FDA feed ban warning letter below). I stress that the August 4, 1997 USA mad cow feed ban and this infamous BSE firewall, was nothing more than ink on paper, it was never enforceable.
I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route. This would further have to be broken down to strain of species and then the route of transmission would further have to be broken down. Accumulation and Transmission are key to the threshold from sub- clinical to clinical disease, and key to all this, is to stop the amplification and transmission of this agent, the spreading of, no matter what strain. In my opinion, to continue with this myth that the U.K. strain of BSE one strain TSE in cows, and the nv/v CJD one strain TSE humans, and the one geographical location source i.e. U.K., and that all the rest of human TSE are just one single strain i.e. sporadic CJD, a happenstance of bad luck that just happens due to a twisted protein that just twisted the wrong way, IN 85%+ OF ALL HUMAN TSEs, when to date there are 6 different phenotypes of sCJD, and growing per Gambetti et al, and that no other animal TSE transmits to humans ??? With all due respect to all Scientist that believe this, I beg to differ. To continue with this masquerade will only continue to spread, expose, and kill, who knows how many more in the years and decades to come. ONE was enough for me, My Mom, hvCJD i.e. Heidenhain Variant CJD, DOD 12/14/97 confirmed, which is nothing more than another mans name added to CJD, like CJD itself, Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker syndrome, just another CJD or human TSE, named after another human. WE are only kidding ourselves with the current diagnostic criteria for human and animal TSE, especially differentiating between the nvCJD vs the sporadic CJD strains and then the GSS strains and also the FFI fatal familial insomnia strains or the ones that mimics one or the other of those TSE? Tissue infectivity and strain typing of the many variants of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously. ...
please see history, and the ever evolving TSE science to date ;
Saturday, June 13, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/04ce2b24-613d-46e6-9802-4131e2bfa6fd
https://web.archive.org/web/20210421175119/https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/04ce2b24-613d-46e6-9802-4131e2bfa6fd
Singeltary Submission SEAC 2007
SEAC SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Minutes of the 99th meeting held on 14th December 2007 Singeltary Submission
This was 22 years to the day Mom died from the Heidenhain Variant of Creutzfeldt Jakob Disease i.e. hvCJD, when i made this submission to SEAC and this was their reply to my questions of concern about cjd in the USA, my how things have changed...terry
SEAC SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Minutes of the 99th meeting held on 14th December 2007
ITEM 8 – PUBLIC QUESTION AND ANSWER SESSION 40. The Chair explained that the purpose of the question and answer session was to give members of the public an opportunity to ask questions related to the work of SEAC. Mr Terry Singeltary (Texas, USA) had submitted a question prior to the meeting, asking: “With the Nor-98 now documented in five different states so far in the USA in 2007, and with the two atypical BSE H-base cases in Texas and Alabama, with both scrapie and chronic wasting disease (CWD) running rampant in the USA, is there any concern from SEAC with the rise of sporadic CJD in the USA from ''unknown phenotype'', and what concerns if any, in relations to blood donations, surgery, optical, and dental treatment, do you have with these unknown atypical phenotypes in both humans and animals in the USA? Does it concern SEAC, or is it of no concern to SEAC? Should it concern USA animal and human health officials?”
41. A member considered that this question appeared to be primarily related to possible links between animal and human TSEs in the USA. There is no evidence that sCJD is increasing in the USA and no evidence of any direct link between TSEs and CJD in the USA. Current evidence does not suggest that CWD is a significant risk to human health. There are unpublished data from a case of human TSE in the USA that are suggestive of an apparently novel form of prion disease with distinct molecular characteristics. However, it is unclear whether the case had been further characterised, if it could be linked to animal TSEs or if other similar cases had been found in the USA or elsewhere. In relation to the possible public health implications of atypical scrapie, H-type BSE and CWD, research was being conducted to investigate possible links and surveillance was in place to detect any changes in human TSEs. Although possible links between these diseases and human TSEs are of concern and require research, there is no evidence to suggest immediate public health action is warranted. The possible human health risks from classical scrapie had been discussed earlier in the meeting. Members noted that there are effective channels of discussion and collaboration on research between USA and European groups. Members agreed it is important to keep a watching brief on new developments on TSEs.
http://web.archive.org/web/20091010132933/http://www.seac.gov.uk/minutes/99.pdf
Singeltary 2000
BMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7226.8/b (Published 01 January 2000) Cite this as: BMJ 2000;320:8
02 January 2000 Terry S Singeltary retired
Rapid Response:
U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well...
In reading your short article about 'Scientist warn of CJD epidemic' news in brief Jan. 1, 2000. I find the findings in the PNAS old news, made famous again. Why is the U.S. still sitting on their butts, ignoring the facts? We have the beginning of a CJD epidemic in the U.S., and the U.S. Gov. is doing everything in it's power to conceal it.
The exact same recipe for B.S.E. existed in the U.S. for years and years. In reading over the Qualitative Analysis of BSE Risk Factors-1, this is a 25 page report by the USDA:APHIS:VS. It could have been done in one page. The first page, fourth paragraph says it all;
"Similarities exist in the two countries usage of continuous rendering technology and the lack of usage of solvents, however, large differences still remain with other risk factors which greatly reduce the potential risk at the national level."
Then, the next 24 pages tries to down-play the high risks of B.S.E. in the U.S., with nothing more than the cattle to sheep ratio count, and the geographical locations of herds and flocks. That's all the evidence they can come up with, in the next 24 pages.
Something else I find odd, page 16;
"In the United Kingdom there is much concern for a specific continuous rendering technology which uses lower temperatures and accounts for 25 percent of total output. This technology was _originally_ designed and imported from the United States. However, the specific application in the production process is _believed_ to be different in the two countries."
A few more factors to consider, page 15;
"Figure 26 compares animal protein production for the two countries. The calculations are based on slaughter numbers, fallen stock estimates, and product yield coefficients. This approach is used due to variation of up to 80 percent from different reported sources. At 3.6 million tons, the United States produces 8 times more animal rendered product than the United Kingdom."
"The risk of introducing the BSE agent through sheep meat and bone meal is more acute in both relative and absolute terms in the United Kingdom (Figures 27 and 28). Note that sheep meat and bone meal accounts for 14 percent, or 61 thousand tons, in the United Kingdom versus 0.6 percent or 22 thousand tons in the United States. For sheep greater than 1 year, this is less than one-tenth of one percent of the United States supply."
"The potential risk of amplification of the BSE agent through cattle meat and bone meal is much greater in the United States where it accounts for 59 percent of total product or almost 5 times more than the total amount of rendered product in the United Kingdom."
Considering, it would only take _one_ scrapie infected sheep to contaminate the feed. Considering Scrapie has run rampant in the U.S. for years, as of Aug. 1999, 950 scrapie infected flocks. Also, Considering only one quarter spoonful of scrapie infected material is lethal to a cow.
Considering all this, the sheep to cow ration is meaningless. As I said, it's 24 pages of B.S.e.
To be continued...
Terry S. Singeltary Sr. Bacliff, Texas USA
Competing interests: No competing interests
https://www.bmj.com/rapid-response/2011/10/28/us-scientist-should-be-concerned-cjd-epidemic-us-well
BMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7220.1312b (Published 13 November 1999) Cite this as: BMJ 1999;319:1312
Rapid Response:
Re: vCJD in the USA * BSE in U.S.
In reading the recent article in the BMJ about the potential BSE tests being developed in the U.S. and Bart Van Everbroeck reply. It does not surprize me, that the U.S. has been concealing vCJD. There have been people dying from CJD, with all the symptoms and pathological findings that resemble U.K. vCJD for some time. It just seems that when there is one found, they seem to change the clarical classification of the disease, to fit their agenda. I have several autopsies, stating kuru type amyloid plaques, one of the victims was 41 years of age. Also, my Mom died a most hideous death, Heidenhain Variant Creutzfeldt Jakob disease.
Her symptoms resemble that of all the U.K. vCJD victims. She would jerk so bad at times, it would take 3 of us to hold her down, while she screamed "God, what's wrong with me, why can't I stop this." 1st of symptoms to death, 10 weeks, she went blind in the first few weeks. But, then they told me that this was just another strain of sporadic CJD. They can call it what ever they want, but I know what I saw, and what she went through. Sporadic, simply means, they do not know.
My neighbors Mom also died from CJD. She had been taking a nutritional supplement which contained the following;
vacuum dried bovine BRAIN, bone meal, bovine EYE, veal bone, bovine liver powder, bovine adrenal, vacuum dried bovine kidney, and vacuum dried porcine stomach. As I said, this woman taking these nutritional supplements, died from CJD.
The particular batch of pills that was located, in which she was taking, was tested. From what I have heard, they came up negative, for the prion protein. But, in the same breath, they said their testing, may not have been strong enough to pick up the infectivity. Plus, she had been taking these type pills for years, so, could it have come from another batch?
CWD is just a small piece of a very big puzzle. I have seen while deer hunting, deer, squirrels and birds, eating from cattle feed troughs where they feed cattle, the high protein cattle by products, at least up until Aug. 4, 1997.
So why would it be so hard to believe that this is how they might become infected with a TSE. Or, even by potentially infected land. It's been well documented that it could be possible, from scrapie. Cats becoming infected with a TSE. Have you ever read the ingredients on the labels of cat and dog food? But, they do not put these tissues from these animals in pharmaceuticals, cosmetics, nutritional supplements, hGH, hPG, blood products, heart valves, and the many more products that come from bovine, ovine, or porcine tissues and organs. So, as I said, this CWD would be a small piece of a very big puzzle. But, it is here, and it most likely has killed. You see, greed is what caused this catastrophe, rendering and feeding practices. But, once Pandora's box was opened, the potential routes of infection became endless.
No BSE in the U.S.A.? I would not be so sure of that considering that since 1990;
Since 1990 the U.S. has raised 1,250,880,700 cattle;
Since 1990 the U.S. has ONLY checked 8,881 cattle brains for BSE, as of Oct. 4, 1999;
There are apprx. 100,000 DOWNER cattle annually in the U.S., that up until Aug. 4, 1997 went to the renders for feed;
Scrapie running rampant for years in the U.S., 950 infected FLOCKS, as of Aug. 1999;
Our feeding and rendering practices have mirrored that of the U.K. for years, some say it was worse. Everything from the downer cattle, to those scrapie infected sheep, to any roadkill, including the city police horse and the circus elephant went to the renders for feed and other products for consumption. Then they only implemented a partial feed ban on Aug. 4, 1997, but pigs, chickens, dogs, and cats, and humans were exempt from that ban. So they can still feed pigs and chickens those potentially TSE tainted by-products, and then they can still feed those by-products back to the cows. I believe it was Dr. Joe Gibbs, that said, the prion protein, can survive the digestinal track. So you have stopped nothing. It was proven in Oprah Winfrey's trial, that Cactus Cattle feeders, sent neurologically ill cattle, some with encephalopathy stamped on the dead slips, were picked up and sent to the renders, along with sheep carcasses. Speaking of autopsies, I have a stack of them, from CJD victims. You would be surprised of the number of them, who ate cow brains, elk brains, deer brains, or hog brains.
I believe all these TSE's are going to be related, and originally caused by the same greedy Industries, and they will be many. Not just the Renders, but you now see, that they are re-using medical devices that were meant for disposal. Some medical institutions do not follow proper auto- claving procedures (even Olympus has put out a medical warning on their endescopes about CJD, and the fact you cannot properly clean these instruments from TSE's), and this is just one product. Another route of infection.
Regardless what the Federal Government in the U.S. says. It's here, I have seen it, and the longer they keep sweeping it under the rug and denying the fact that we have a serious problem, one that could surpass aids (not now, but in the years to come, due to the incubation period), they will be responsible for the continued spreading of this deadly disease.
It's their move, it's CHECK, but once CHECKMATE has been called, how many thousands or millions, will be at risk or infected or even dead. You can't play around with these TSE's. I cannot stress that enough. They are only looking at body bags, and the fact the count is so low. But, then you have to look at the fact it is not a reportable disease in most states, mis-diagnosis, no autopsies performed. The fact that their one-in-a- million theory is a crude survey done about 5 years ago, that's a joke, under the above circumstances. A bad joke indeed........
The truth will come, but how many more have to die such a hideous death. It's the Government's call, and they need to make a serious move, soon. This problem, potential epidemic, is not going away, by itself.
Terry S. Singeltary Sr.
Bacliff, Texas 77518 USA
flounder@wt.net
Competing interests: No competing interests
https://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us
1999 Re: vCJD in the USA * BSE in U.S. BMJ 1999;319:1312 Singeltary
https://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us
RE: re-Human Prion Diseases in the United States part 2 flounder replied to flounder on 02 Jan 2010 at 21:26 GMT
I would kindly like to add to my initial concerns, something I brought up years ago, and I believe that still hold true today, more so even than when I first stated these concerns in 2003 ;
***> routine passive mortality CJD surveillance USA ?
***> THIS has been proven not to be very useful in the U.K.;
THE EPIDEMIOLOGY OF CJD RG WILL 1984 (182 PAGES)
snip...
One reason for this was the _inaccuracy_ in coding of cases correctly certified as CJD Coding is carried out by staff who are not medically qualified and it is not surprising that coding errors occur in the processing of large numbers of certificates. In 1982, 12,000 certificates per week were processed at the office of population censuses and surveys by 15 coders and 6 checkers (Alderson et al., 1983). The occurrence of both inter- and intra-observer coding errors has been described (Curb et al., 1983) and the _inaccuracies_ of BOTH certification and coding discovered in this study _support_ the introduction of a more accurate system of death certificates and a more detailed and specific coding system...
snip...
http://web.archive.org/web/20040521215716/http://www.bseinquiry.gov.uk/files/mb/m26/tab01.pdf
Draft Proposal For The Monitoring of Creutzfeldt-Kakob Disease 1989 Dr. R. Will
snip...
IDENTIFICATION OF CASES
Cases of CJD may be identified from death certificates, but this alone is unlikely to provide adequate monitoring. ERRORS are made in certification and diagnosis; in the Oxford study death certificates were obtained on a series of known confirmed cases and CJD was mentioned in only 66% of certificates. In another series of 175 certified cases, 42 patients were judged not to have suffered from CJD after examination of case notes (7)...
full text;
http://web.archive.org/web/20050526035006/http://www.bseinquiry.gov.uk/files/yb/1989/05/00005001.pdf
CJD Questionnaire
F. MEDICATIONS, has Subject taken any medications regularly, (if yes, record the date, name of the medication, the reason for taking it, and route of administration) prompt for prescription drugs, including insulin and type. Prompt for hormone therapy or nutritional supplements including oral contraceptives and hormone replacement therapy: Prompt for homeopathic/herbal therapy: Prompt for eye drops SUMMARY OF ABOVE RESPONSES; HAS THE SUBJECT BEEN EXPOSED TO ONE OF THE MEDICATIONS OF BOVINE OR OVINE ORIGIN, AND OR ANY DESICCATED ANIMAL ORIGIN? G. Has Subject ever been tested for allergy using needles? H. Has Subject ever received a treatment involving a course of injections? (If yes, record year, name of therapy, frequency, reason)
https://web.archive.org/web/20090506075100/http://www.bseinquiry.gov.uk/files/mb/m26/tab04.pdf
NOT to open up old wounds, but here is my 23 years of endeavors to get the USA to have a CJD Questionnaire for every family of a person whom died of cjd tse prion in the USA in every State, pertaining to real questions of all the potential routes of CJD in that questionnaire. seems i have failed terribly. there was great debate, much anguish, and i did take it personally, when others took credit for what i had been trying to get done. but this was long ago, and today the CJD Foundation seems to be working hard to change there old ways, and seem to be looking to find the routes of sporadic cjd as well. this is just that history, like it or not...kind regards, terry
THE MAKING OF THE USA CJD QUESTIONNAIRE
https://cjdquestionnaire.blogspot.com/2015/10/cjd-foundation-creutzfeldt-jakob.html
https://creutzfeldt-jakob-disease.blogspot.com/2012/03/cjd-foundation-cwru-gambetti-familial.html
https://cjdquestionnaire.blogspot.com/2009/
http://cjdquestionnaire.blogspot.com/2007/11/cjd-questionnaire.html
https://cjdquestionnaire.blogspot.com/2007/
http://cjdquestionnaire.blogspot.com/
MONDAY, SEPTEMBER 11, 2023
Professor John Collinge on tackling prion diseases sCJD around 1 in 5000 deaths worldwide
“The best-known human prion disease is sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia which accounts for around 1 in 5000 deaths worldwide.”
Most importantly with respect to neurodegeneration and dementia in humans, it has been established that similar so-called “prion-like” mechanisms are involved in much commoner conditions including Alzheimer’s and Parkinson’s diseases.
In Alzheimer’s disease (AD) for example, two proteins in the brain, amyloid-beta and tau can form self-propagating assemblies which spread in the brain.
Indeed, we reported in two articles in Nature that the amyloid-beta pathology seen in AD can be transmissible between humans in rare circumstances causing the newly recognised condition iatrogenic cerebral amyloid angiopathy.
There is accumulating evidence also for iatrogenic AD.
https://www.ucl.ac.uk/brain-sciences/research/dementia-ucl-priority/professor-john-collinge-tackling-prion-diseases
2001 Singeltary Alzheimer’s and sCJD
Singeltary 2001
Subject: CJD or Alzheimer's or the same ???
Date: Sun, 29 Apr 2001 12:45:28 -0700
From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
Bovine Spongiform Encephalopathy
Greetings List,
thought some might be interested in this. I have always wondered if CJD and or all TSEs and Alzheimer's could be linked. i have been of the opinion that Alzheimer's is a TSE for a long time, just at the low end of the titre of infectivity scale. i also believe in the accumulation theory. by dose, you could be killed by one sitting, or one injection, or one whatever, depending on the titre of infectivity of that whatever. on the other hand, if the dose is not a lethal dose, over a period of time, the accumulation will become lethal (if consumption continued), and i believe the route/source/titre of infectivity, will be a key roll to the incubation period, and symptoms.
just my opinion...snip…end
Snip…
https://creutzfeldt-jakob-disease.blogspot.com/2023/09/professor-john-collinge-on-tackling.html
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/933cc83a-a384-45c3-b3b2-336882c30f9d
https://creutzfeldt-jakob-disease.blogspot.com/2023/09/professor-john-collinge-on-tackling.html
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Published: 09 September 2015
Nature 525, 247?250 (10 September 2015)
Terry S. Singeltary Sr. 7 December 2015, 14:27
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
Terry S. Singeltary Sr. 7 December 2015, 14:27
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html
I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.
First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.
Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.
where have we all heard this before? its been well documented via the BSE Inquiry. have they not learned a lesson from the last time?
we have seen this time and time again in England (and other Countrys) with the BSE mad cow TSE Prion debacle.
That ‘anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.
The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ? who got pooled extracts injected from thousands of cadavers ? were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.
That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find ‘alarming’ is pathetic.
Sounds like the journalists had it right in the first place: ‘Alzheimers may be a transmissible infection’ in The Independent to ‘You can catch Alzheimers’ in The Daily Mirror or ‘Alzheimers bombshell’ in The Daily Express
if not for the journalist, the layperson would not know about these important findings.
where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?
when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.
to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimers, the price of poker goes up drastically.
so, who makes that final decision, and how many more decades do we have to wait?
the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?
Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.
FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.
in my opinion, it’s one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.
greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it’s bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.
my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimers of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.
I kindly wish to remind the public of the past, and a possible future we all hopes never happens again.
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer?s and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media attention.]
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
http://www.plosone.org/annotation/listThread.action?root=82860
please see more of this history and references there from (these blogs are for educational use, I do not advertise or make money from this. just made a promise to mom dod 12/14/97 hvCJD, never forget, and never let them forget.)
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Singeltary Submission to Nature;
https://www.nature.com/articles/nature15369#article-comments
http://betaamyloidcjd.blogspot.com/2015/10/alzheimergate-re-evidence-for-human.html
https://www.nature.com/articles/nature15369#article-comments
SUNDAY, JUNE 7, 2026
Creutzfeldt–Jakob disease is an Alzheimer’s disease-related dementia
https://betaamyloidcjd.blogspot.com/2026/06/creutzfeldtjakob-disease-is-alzheimers.html
2026 USDA EXPLANATORY NOTES ANIMAL AND PLANT HEALTH INSPECTION SERVICE CWD, Scrapie, BSE, and CJD, Singeltary Review
https://transmissiblespongiformencephalopathy.blogspot.com/2026/11/2026-usda-explanatory-notes-animal-and.html
https://prpsc.proboards.com/thread/268/2026-explanatory-notes-aphis-review
So, this is what we leave our children and grandchildren?
what if?
Terry S. Singeltary Sr., Bacliff, Tx. 77518
SEAC SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Minutes of the 99th meeting held on 14th December 2007 Singeltary Submission
This was 22 years to the day Mom died from the Heidenhain Variant of Creutzfeldt Jakob Disease i.e. hvCJD, when i made this submission to SEAC and this was their reply to my questions of concern about cjd in the USA, my how things have changed...terry
SEAC SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Minutes of the 99th meeting held on 14th December 2007
ITEM 8 – PUBLIC QUESTION AND ANSWER SESSION 40. The Chair explained that the purpose of the question and answer session was to give members of the public an opportunity to ask questions related to the work of SEAC. Mr Terry Singeltary (Texas, USA) had submitted a question prior to the meeting, asking: “With the Nor-98 now documented in five different states so far in the USA in 2007, and with the two atypical BSE H-base cases in Texas and Alabama, with both scrapie and chronic wasting disease (CWD) running rampant in the USA, is there any concern from SEAC with the rise of sporadic CJD in the USA from ''unknown phenotype'', and what concerns if any, in relations to blood donations, surgery, optical, and dental treatment, do you have with these unknown atypical phenotypes in both humans and animals in the USA? Does it concern SEAC, or is it of no concern to SEAC? Should it concern USA animal and human health officials?”
41. A member considered that this question appeared to be primarily related to possible links between animal and human TSEs in the USA. There is no evidence that sCJD is increasing in the USA and no evidence of any direct link between TSEs and CJD in the USA. Current evidence does not suggest that CWD is a significant risk to human health. There are unpublished data from a case of human TSE in the USA that are suggestive of an apparently novel form of prion disease with distinct molecular characteristics. However, it is unclear whether the case had been further characterised, if it could be linked to animal TSEs or if other similar cases had been found in the USA or elsewhere. In relation to the possible public health implications of atypical scrapie, H-type BSE and CWD, research was being conducted to investigate possible links and surveillance was in place to detect any changes in human TSEs. Although possible links between these diseases and human TSEs are of concern and require research, there is no evidence to suggest immediate public health action is warranted. The possible human health risks from classical scrapie had been discussed earlier in the meeting. Members noted that there are effective channels of discussion and collaboration on research between USA and European groups. Members agreed it is important to keep a watching brief on new developments on TSEs.
http://web.archive.org/web/20091010132933/http://www.seac.gov.uk/minutes/99.pdf
Singeltary 2000
BMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7226.8/b (Published 01 January 2000) Cite this as: BMJ 2000;320:8
02 January 2000 Terry S Singeltary retired
Rapid Response:
U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well...
In reading your short article about 'Scientist warn of CJD epidemic' news in brief Jan. 1, 2000. I find the findings in the PNAS old news, made famous again. Why is the U.S. still sitting on their butts, ignoring the facts? We have the beginning of a CJD epidemic in the U.S., and the U.S. Gov. is doing everything in it's power to conceal it.
The exact same recipe for B.S.E. existed in the U.S. for years and years. In reading over the Qualitative Analysis of BSE Risk Factors-1, this is a 25 page report by the USDA:APHIS:VS. It could have been done in one page. The first page, fourth paragraph says it all;
"Similarities exist in the two countries usage of continuous rendering technology and the lack of usage of solvents, however, large differences still remain with other risk factors which greatly reduce the potential risk at the national level."
Then, the next 24 pages tries to down-play the high risks of B.S.E. in the U.S., with nothing more than the cattle to sheep ratio count, and the geographical locations of herds and flocks. That's all the evidence they can come up with, in the next 24 pages.
Something else I find odd, page 16;
"In the United Kingdom there is much concern for a specific continuous rendering technology which uses lower temperatures and accounts for 25 percent of total output. This technology was _originally_ designed and imported from the United States. However, the specific application in the production process is _believed_ to be different in the two countries."
A few more factors to consider, page 15;
"Figure 26 compares animal protein production for the two countries. The calculations are based on slaughter numbers, fallen stock estimates, and product yield coefficients. This approach is used due to variation of up to 80 percent from different reported sources. At 3.6 million tons, the United States produces 8 times more animal rendered product than the United Kingdom."
"The risk of introducing the BSE agent through sheep meat and bone meal is more acute in both relative and absolute terms in the United Kingdom (Figures 27 and 28). Note that sheep meat and bone meal accounts for 14 percent, or 61 thousand tons, in the United Kingdom versus 0.6 percent or 22 thousand tons in the United States. For sheep greater than 1 year, this is less than one-tenth of one percent of the United States supply."
"The potential risk of amplification of the BSE agent through cattle meat and bone meal is much greater in the United States where it accounts for 59 percent of total product or almost 5 times more than the total amount of rendered product in the United Kingdom."
Considering, it would only take _one_ scrapie infected sheep to contaminate the feed. Considering Scrapie has run rampant in the U.S. for years, as of Aug. 1999, 950 scrapie infected flocks. Also, Considering only one quarter spoonful of scrapie infected material is lethal to a cow.
Considering all this, the sheep to cow ration is meaningless. As I said, it's 24 pages of B.S.e.
To be continued...
Terry S. Singeltary Sr. Bacliff, Texas USA
Competing interests: No competing interests
https://www.bmj.com/rapid-response/2011/10/28/us-scientist-should-be-concerned-cjd-epidemic-us-well
BMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7220.1312b (Published 13 November 1999) Cite this as: BMJ 1999;319:1312
Rapid Response:
Re: vCJD in the USA * BSE in U.S.
In reading the recent article in the BMJ about the potential BSE tests being developed in the U.S. and Bart Van Everbroeck reply. It does not surprize me, that the U.S. has been concealing vCJD. There have been people dying from CJD, with all the symptoms and pathological findings that resemble U.K. vCJD for some time. It just seems that when there is one found, they seem to change the clarical classification of the disease, to fit their agenda. I have several autopsies, stating kuru type amyloid plaques, one of the victims was 41 years of age. Also, my Mom died a most hideous death, Heidenhain Variant Creutzfeldt Jakob disease.
Her symptoms resemble that of all the U.K. vCJD victims. She would jerk so bad at times, it would take 3 of us to hold her down, while she screamed "God, what's wrong with me, why can't I stop this." 1st of symptoms to death, 10 weeks, she went blind in the first few weeks. But, then they told me that this was just another strain of sporadic CJD. They can call it what ever they want, but I know what I saw, and what she went through. Sporadic, simply means, they do not know.
My neighbors Mom also died from CJD. She had been taking a nutritional supplement which contained the following;
vacuum dried bovine BRAIN, bone meal, bovine EYE, veal bone, bovine liver powder, bovine adrenal, vacuum dried bovine kidney, and vacuum dried porcine stomach. As I said, this woman taking these nutritional supplements, died from CJD.
The particular batch of pills that was located, in which she was taking, was tested. From what I have heard, they came up negative, for the prion protein. But, in the same breath, they said their testing, may not have been strong enough to pick up the infectivity. Plus, she had been taking these type pills for years, so, could it have come from another batch?
CWD is just a small piece of a very big puzzle. I have seen while deer hunting, deer, squirrels and birds, eating from cattle feed troughs where they feed cattle, the high protein cattle by products, at least up until Aug. 4, 1997.
So why would it be so hard to believe that this is how they might become infected with a TSE. Or, even by potentially infected land. It's been well documented that it could be possible, from scrapie. Cats becoming infected with a TSE. Have you ever read the ingredients on the labels of cat and dog food? But, they do not put these tissues from these animals in pharmaceuticals, cosmetics, nutritional supplements, hGH, hPG, blood products, heart valves, and the many more products that come from bovine, ovine, or porcine tissues and organs. So, as I said, this CWD would be a small piece of a very big puzzle. But, it is here, and it most likely has killed. You see, greed is what caused this catastrophe, rendering and feeding practices. But, once Pandora's box was opened, the potential routes of infection became endless.
No BSE in the U.S.A.? I would not be so sure of that considering that since 1990;
Since 1990 the U.S. has raised 1,250,880,700 cattle;
Since 1990 the U.S. has ONLY checked 8,881 cattle brains for BSE, as of Oct. 4, 1999;
There are apprx. 100,000 DOWNER cattle annually in the U.S., that up until Aug. 4, 1997 went to the renders for feed;
Scrapie running rampant for years in the U.S., 950 infected FLOCKS, as of Aug. 1999;
Our feeding and rendering practices have mirrored that of the U.K. for years, some say it was worse. Everything from the downer cattle, to those scrapie infected sheep, to any roadkill, including the city police horse and the circus elephant went to the renders for feed and other products for consumption. Then they only implemented a partial feed ban on Aug. 4, 1997, but pigs, chickens, dogs, and cats, and humans were exempt from that ban. So they can still feed pigs and chickens those potentially TSE tainted by-products, and then they can still feed those by-products back to the cows. I believe it was Dr. Joe Gibbs, that said, the prion protein, can survive the digestinal track. So you have stopped nothing. It was proven in Oprah Winfrey's trial, that Cactus Cattle feeders, sent neurologically ill cattle, some with encephalopathy stamped on the dead slips, were picked up and sent to the renders, along with sheep carcasses. Speaking of autopsies, I have a stack of them, from CJD victims. You would be surprised of the number of them, who ate cow brains, elk brains, deer brains, or hog brains.
I believe all these TSE's are going to be related, and originally caused by the same greedy Industries, and they will be many. Not just the Renders, but you now see, that they are re-using medical devices that were meant for disposal. Some medical institutions do not follow proper auto- claving procedures (even Olympus has put out a medical warning on their endescopes about CJD, and the fact you cannot properly clean these instruments from TSE's), and this is just one product. Another route of infection.
Regardless what the Federal Government in the U.S. says. It's here, I have seen it, and the longer they keep sweeping it under the rug and denying the fact that we have a serious problem, one that could surpass aids (not now, but in the years to come, due to the incubation period), they will be responsible for the continued spreading of this deadly disease.
It's their move, it's CHECK, but once CHECKMATE has been called, how many thousands or millions, will be at risk or infected or even dead. You can't play around with these TSE's. I cannot stress that enough. They are only looking at body bags, and the fact the count is so low. But, then you have to look at the fact it is not a reportable disease in most states, mis-diagnosis, no autopsies performed. The fact that their one-in-a- million theory is a crude survey done about 5 years ago, that's a joke, under the above circumstances. A bad joke indeed........
The truth will come, but how many more have to die such a hideous death. It's the Government's call, and they need to make a serious move, soon. This problem, potential epidemic, is not going away, by itself.
Terry S. Singeltary Sr.
Bacliff, Texas 77518 USA
flounder@wt.net
Competing interests: No competing interests
https://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us
1999 Re: vCJD in the USA * BSE in U.S. BMJ 1999;319:1312 Singeltary
https://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us
RE: re-Human Prion Diseases in the United States part 2 flounder replied to flounder on 02 Jan 2010 at 21:26 GMT
I would kindly like to add to my initial concerns, something I brought up years ago, and I believe that still hold true today, more so even than when I first stated these concerns in 2003 ;
***> routine passive mortality CJD surveillance USA ?
***> THIS has been proven not to be very useful in the U.K.;
THE EPIDEMIOLOGY OF CJD RG WILL 1984 (182 PAGES)
snip...
One reason for this was the _inaccuracy_ in coding of cases correctly certified as CJD Coding is carried out by staff who are not medically qualified and it is not surprising that coding errors occur in the processing of large numbers of certificates. In 1982, 12,000 certificates per week were processed at the office of population censuses and surveys by 15 coders and 6 checkers (Alderson et al., 1983). The occurrence of both inter- and intra-observer coding errors has been described (Curb et al., 1983) and the _inaccuracies_ of BOTH certification and coding discovered in this study _support_ the introduction of a more accurate system of death certificates and a more detailed and specific coding system...
snip...
http://web.archive.org/web/20040521215716/http://www.bseinquiry.gov.uk/files/mb/m26/tab01.pdf
Draft Proposal For The Monitoring of Creutzfeldt-Kakob Disease 1989 Dr. R. Will
snip...
IDENTIFICATION OF CASES
Cases of CJD may be identified from death certificates, but this alone is unlikely to provide adequate monitoring. ERRORS are made in certification and diagnosis; in the Oxford study death certificates were obtained on a series of known confirmed cases and CJD was mentioned in only 66% of certificates. In another series of 175 certified cases, 42 patients were judged not to have suffered from CJD after examination of case notes (7)...
full text;
http://web.archive.org/web/20050526035006/http://www.bseinquiry.gov.uk/files/yb/1989/05/00005001.pdf
CJD Questionnaire
F. MEDICATIONS, has Subject taken any medications regularly, (if yes, record the date, name of the medication, the reason for taking it, and route of administration) prompt for prescription drugs, including insulin and type. Prompt for hormone therapy or nutritional supplements including oral contraceptives and hormone replacement therapy: Prompt for homeopathic/herbal therapy: Prompt for eye drops SUMMARY OF ABOVE RESPONSES; HAS THE SUBJECT BEEN EXPOSED TO ONE OF THE MEDICATIONS OF BOVINE OR OVINE ORIGIN, AND OR ANY DESICCATED ANIMAL ORIGIN? G. Has Subject ever been tested for allergy using needles? H. Has Subject ever received a treatment involving a course of injections? (If yes, record year, name of therapy, frequency, reason)
https://web.archive.org/web/20090506075100/http://www.bseinquiry.gov.uk/files/mb/m26/tab04.pdf
NOT to open up old wounds, but here is my 23 years of endeavors to get the USA to have a CJD Questionnaire for every family of a person whom died of cjd tse prion in the USA in every State, pertaining to real questions of all the potential routes of CJD in that questionnaire. seems i have failed terribly. there was great debate, much anguish, and i did take it personally, when others took credit for what i had been trying to get done. but this was long ago, and today the CJD Foundation seems to be working hard to change there old ways, and seem to be looking to find the routes of sporadic cjd as well. this is just that history, like it or not...kind regards, terry
THE MAKING OF THE USA CJD QUESTIONNAIRE
https://cjdquestionnaire.blogspot.com/2015/10/cjd-foundation-creutzfeldt-jakob.html
https://creutzfeldt-jakob-disease.blogspot.com/2012/03/cjd-foundation-cwru-gambetti-familial.html
https://cjdquestionnaire.blogspot.com/2009/
http://cjdquestionnaire.blogspot.com/2007/11/cjd-questionnaire.html
https://cjdquestionnaire.blogspot.com/2007/
http://cjdquestionnaire.blogspot.com/
MONDAY, SEPTEMBER 11, 2023
Professor John Collinge on tackling prion diseases sCJD around 1 in 5000 deaths worldwide
“The best-known human prion disease is sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia which accounts for around 1 in 5000 deaths worldwide.”
Most importantly with respect to neurodegeneration and dementia in humans, it has been established that similar so-called “prion-like” mechanisms are involved in much commoner conditions including Alzheimer’s and Parkinson’s diseases.
In Alzheimer’s disease (AD) for example, two proteins in the brain, amyloid-beta and tau can form self-propagating assemblies which spread in the brain.
Indeed, we reported in two articles in Nature that the amyloid-beta pathology seen in AD can be transmissible between humans in rare circumstances causing the newly recognised condition iatrogenic cerebral amyloid angiopathy.
There is accumulating evidence also for iatrogenic AD.
https://www.ucl.ac.uk/brain-sciences/research/dementia-ucl-priority/professor-john-collinge-tackling-prion-diseases
2001 Singeltary Alzheimer’s and sCJD
Singeltary 2001
Subject: CJD or Alzheimer's or the same ???
Date: Sun, 29 Apr 2001 12:45:28 -0700
From: "Terry S. Singeltary Sr." Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
Bovine Spongiform Encephalopathy
Greetings List,
thought some might be interested in this. I have always wondered if CJD and or all TSEs and Alzheimer's could be linked. i have been of the opinion that Alzheimer's is a TSE for a long time, just at the low end of the titre of infectivity scale. i also believe in the accumulation theory. by dose, you could be killed by one sitting, or one injection, or one whatever, depending on the titre of infectivity of that whatever. on the other hand, if the dose is not a lethal dose, over a period of time, the accumulation will become lethal (if consumption continued), and i believe the route/source/titre of infectivity, will be a key roll to the incubation period, and symptoms.
just my opinion...snip…end
Snip…
https://creutzfeldt-jakob-disease.blogspot.com/2023/09/professor-john-collinge-on-tackling.html
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/933cc83a-a384-45c3-b3b2-336882c30f9d
https://creutzfeldt-jakob-disease.blogspot.com/2023/09/professor-john-collinge-on-tackling.html
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Published: 09 September 2015
Nature 525, 247?250 (10 September 2015)
Terry S. Singeltary Sr. 7 December 2015, 14:27
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
Terry S. Singeltary Sr. 7 December 2015, 14:27
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html
I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.
First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.
Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.
where have we all heard this before? its been well documented via the BSE Inquiry. have they not learned a lesson from the last time?
we have seen this time and time again in England (and other Countrys) with the BSE mad cow TSE Prion debacle.
That ‘anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.
The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ? who got pooled extracts injected from thousands of cadavers ? were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.
That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find ‘alarming’ is pathetic.
Sounds like the journalists had it right in the first place: ‘Alzheimers may be a transmissible infection’ in The Independent to ‘You can catch Alzheimers’ in The Daily Mirror or ‘Alzheimers bombshell’ in The Daily Express
if not for the journalist, the layperson would not know about these important findings.
where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?
when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.
to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimers, the price of poker goes up drastically.
so, who makes that final decision, and how many more decades do we have to wait?
the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?
Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.
FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.
in my opinion, it’s one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.
greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it’s bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.
my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimers of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.
I kindly wish to remind the public of the past, and a possible future we all hopes never happens again.
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer?s and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media attention.]
http://web.archive.org/web/20030714222309/www.bseinquiry.gov.uk/files/yb/1992/12/16005001.pdf
http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
http://www.plosone.org/annotation/listThread.action?root=82860
please see more of this history and references there from (these blogs are for educational use, I do not advertise or make money from this. just made a promise to mom dod 12/14/97 hvCJD, never forget, and never let them forget.)
re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Singeltary Submission to Nature;
https://www.nature.com/articles/nature15369#article-comments
http://betaamyloidcjd.blogspot.com/2015/10/alzheimergate-re-evidence-for-human.html
https://www.nature.com/articles/nature15369#article-comments
SUNDAY, JUNE 7, 2026
Creutzfeldt–Jakob disease is an Alzheimer’s disease-related dementia
https://betaamyloidcjd.blogspot.com/2026/06/creutzfeldtjakob-disease-is-alzheimers.html
2026 USDA EXPLANATORY NOTES ANIMAL AND PLANT HEALTH INSPECTION SERVICE CWD, Scrapie, BSE, and CJD, Singeltary Review
https://transmissiblespongiformencephalopathy.blogspot.com/2026/11/2026-usda-explanatory-notes-animal-and.html
https://prpsc.proboards.com/thread/268/2026-explanatory-notes-aphis-review
So, this is what we leave our children and grandchildren?
what if?
Terry S. Singeltary Sr., Bacliff, Tx. 77518
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.