Tuesday, May 21, 2013

CJD, TSE, PRION, BLOOD Abstracts of the 23rd Regional Congress of the International Society of Blood Transfusion, Amsterdam, The Netherlands, June 2-5, 2013

Abstracts of the 23rd Regional Congress of the International Society of Blood Transfusion, Amsterdam, The Netherlands, June 2-5, 2013 Oral Abstracts Oral Abstracts (pages 1–64) Article first published online: 20 MAY 2013 | DOI: 10.1111/vox.12047





1D-H08-02




CURRENT PERSPECTIVES IN TRANSFUSION-TRANSMITTED INFECTIOUS DISEASES: EMERGING AND IMPORTED INFECTIONS, INCLUDING PARASITES


Stramer SL


American Red Cross, Gaithersburg, MD, United States of America


Background: In August 2009, a group from the AABB (Stramer et al., Transfusion 2009;99:1S-29S, Emerging Infectious Disease Agents and their Potential Threat to Transfusion Safety; http://www.aabb.org/resources/bct/eid/Pages/default.aspx) published a Supplement to Transfusion that reviewed the definition and background of emerging infectious disease (EID) agents that pose a real or theoretical threat to transfusion safety, but for which an existing effective intervention is lacking. The necessary attributes for transfusion transmission were outlined including: presence of the agent in blood during an asymptomatic phase in the donor, the agent’s survival/ persistence in blood during processing/storage, and lastly that the agent must be recognized as responsible for a clinically apparent outcome in at least a proportion of recipients who become infected. Without these attributes, agents are not considered as a transfusion-transmission threat and were excluded. Sixty-eight such agents were identified with enough evidence/likelihood of transfusion transmission (e.g. blood phase) and potential for clinical disease to warrant further consideration. In the Supplement, Fact Sheets (FS) were published providing information on: agent classification; background on the disease agent’s importance; the clinical syndromes/ diseases caused; transmission modes (including vectors/reservoirs); likelihood of transfusion transmission, and if proven to be transfusion transmitted, information on known cases; the feasibility and predicted success of interventions that could be used donor screening (questioning) and tests available for diagnostics or that could be adapted for donor screening; and finally, the efficacy, if known, of inactivation methods for plasma-derived products. The Supplement also included a separate section on pathogen reduction technologies for all blood components using published data.
 
 
Agents were prioritized relative to their scientific/epidemiologic threat as well as their perceived threat to the community including concerns expressed by the regulators of blood.
 
 
Agents given the highest priority due to a known transfusiontransmission threat and severe/fatal disease in recipients were the vCJD prion, dengue viruses and the obligate red-cell parasite that causes babesiosis (B. microti and related babesia).
 
 
Although the focus of the Supplement was towards the United States and Canada, many of the agents (and the process) are applicable worldwide. Next steps: Since the publication of the Supplement, five new FSs (yellow fever viruses-including vaccine breakthrough infections, miscellaneous arboviruses, XMRV-including a comprehensive table of published literature, and human parvoviruses/ bocaviruses other than B19) were added and 11 existing FSs updated (babesia, bartonella, chronic wasting disease-CWD, human prions other than vCJD, vCJD, Coxiella burnetii-the agent of Q fever, dengue viruses, HEV, Japanese encephalitis- JE complex, tick-borne encephalitis viruses-TBEV, and human parvovirus B19). Also, tables were released outlining pathogen reduction clinical trials/results (published) and availability/commercial routine use of such technologies by country for platelets, plasma, red cells and whole blood. Of necessity, the list of EID agents is not, and can never be, exhaustive due to the nature of emergence. We recognized that a system of assessing the risk/threat of EIDs for their potential impact on blood safety and availability must include a process for monitoring, identification, evaluation, estimating severity, risk assessments and intervention development. Thus, we are now developing a ‘toolkit’ containing the necessary ‘tools’ from EID monitoring (horizon scanning) to validation/effectiveness evaluations of interventions. Our goal is, ‘to develop a systematic approach to risk assessment and intervention development for the impact of emerging infectious upon blood safety in North America. The system is primarily intended to educate and advise AABB members about risks and interventions in a timely and accurate fashion. Secondary audiences include North American blood systems, blood services and transfusion services’. Certainly this toolkit may be adapted to the needs of ISBT members. Conclusions: The process and final product (toolkit) including methods to monitor EID agent emergence, identification/recognition of a transfusion-transmission threat, methods for quantitative risk assessments, and the appropriate management of such threats should be considered for implementation by all blood systems.






3B-PL6


EVALUATION OF NEURODEGENERATIVE DISEASES AS A THREAT TO THE BLOOD SUPPLY


Edgren G1,2 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 2Department of Hematology, Karolinska University Hospital, Stockholm, Sweden


Background: During recent years, evidence has been accumulating that protein misfolding is central in the causation of a range of neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Considering for example AD, where one of the hallmark features is the aggregation of aberrantly misfolded proteins in the brain, which seems to propagate through the brain in an infectionlike process. Similar observations have been made for Parkinson’s disease, where intrastriatal inoculation of misfolded a-Synuclein – the principal component of Lewy bodies – initiates Parkinson-like neurodegeneration in mice. Similarities with prion diseases have been noted. This is especially disconcerting in light of evidence that variant Creutzfeldt-Jakob disease (vCJD), which could also be characterized as a misfolded protein disease, is transfusion transmittable in sheep – even with blood taken during the symptom free phase of infection – and might have been transmitted by transfusions in humans. As such, the possibility of transfusion transmission of several neurodegenerative disorders is a relevant concern. Aims: To investigate the possible consequences for the blood supply, we assessed the occurrence of a selected range of neurodegenerative diseases in Scandinavian blood donors and possible transfusion transmission of AD.


Methods: The analyses were all based on the Scandinavian donations and transfusions (SCANDAT) database which records the entire computerized blood donation and transfusion history in Sweden and Denmark. We identified all blood donors who had performed at least one whole blood, plasma or platelet donation between 1968 and 2002, and their respective transfusion recipients. Data on donors and transfused patients was linked with national inpatient and cause of death registers to ascertain the occurrence of AD, PD, Amyotrophic lateral sclerosis (ALS) and Dementia of any type. The probability that a particular donation was made by a donor who later developed one of these disorders within 10, 20 or 25 years, was estimated as cumulative incidences using the Kaplan–Meier method. Follow-up was extended until death, emigration or end of follow-up. We also investigated possible transmission of AD by comparing the incidence of AD in recipients of blood from donors who went on to develop AD and recipients of blood from donors who did not develop AD. Transmission analyses were adjusted for necessary confounding factors.


Results: In all, we included 1.1 million blood donors, followed over 13 million person years. A total of 730 donors developed AD, 827 PD, 338 ALS and 2418 Dementia. The probability that a donation was made by a donor who developed AD within 10, 20 and 25 years was 0.03%, 0.19% and 0.45%. For PD, probabilities were 0.03%, 0.22% and 0.45%, and for ALS, 0.02%, 0.07%, and 0.11%. For Dementia, estimates were 0.08%, 0.63%, and 1.44%. Finally, there was no evidence of AD transmission (relative risk, 1.00; 95% CI, 0.78–1.28)


Conclusions: Even when considering latencies as long as 25 years, very few donations are made by donors who go on to develop a neurodegenerative disease. Importantly, we see no association between AD occurrence in donors and their respective recipients, indicating that such transmission is unlikely.




Donor Health and Safey – Infectious Uncertainties





3D-S26-01


AN AMPLIFICATION ASSAY FOR THE PRESYMPTOMATIC DETECTION OF PRION IN BLOOD


Segarra C1, Bougard D1, Beringue V2 and Coste J1 1Etablissement Francais du Sang Pyr en ees-M editerran ee R&D TransDiag, Montpellier, France 2UR892 VIM, Institut National de Recherche Agronomique, Jouy-en-Josas, France


Background: Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are neurodegenerative diseases including the variant of Creutzfeldt-Jakob disease (vCJD) in humans. The central event of these diseases would be the conformational change of a normal cellular protein PrPC into an infectious form PrPTSE. It is now evident that TSEs are transmissible by blood transfusion and this has raised concerns that a reservoir of infectious asymptomatic people could exist in the blood donor population. Until now, no screening test could detect the infectious agent in blood before the onset of clinical signs of disease.


Aims: The objective of this study is to develop a sensitive and specific test that enables the detection of PrPTSE in the blood during the presymptomatic phase of TSE.


Methods: The detection assay comprises three major steps: (i) a ligand-coated bead pre-analytical step in order to concentrate PrPTSE from the different blood components and to remove inhibitory factors which can interfere in the amplification; (ii) a PrPTSE amplification by serial PMCA using transgenic mouse brain homogenate as substrate and (iii) a specific detection of the amplified PrPTSE by immuno-blotting after partial proteinase K digestion. The sample volume has been optimized for 500 ll of plasma and for 25–50 ll of buffy-coat. Whole blood samples from infected sheep collected during preclinical and clinical phases of scrapie were processed in buffy-coat, white blood cells (WBC) and plasma.


Results: PMCA assay allowed detection of PrPTSE in: (i) the WBC of four sheep at the acute phase of scrapie with a 100% sensitivity and specificity, (ii) in the plasma and buffy coat collected in the asymptomatic phase of the disease. Summary/Conclusions: The expected level of sensitivity for the detection of prion in the blood was reached. This assay is currently evaluated as a confirmatory detection test for the presence of the vCJD agent in human blood. The next step will be to perform prevalence studies by analysing panels of at-risk populations.










Poster Abstracts Poster Abstracts (pages 65–299)


Article first published online: 20 MAY 2013 | DOI: 10.1111/vox.12048






P-368


IS ALZHEIMER’S DISEASE A PRION DISEASE?


Segarra C and Coste J


Etablissement Francais du Sang Pyr en ees-M editerran ee R&D TransDiag, Montpellier, France


Alzheimer’s disease (AD) is the most common type of senile dementia, mainly affecting individuals over 65 years old. Disease manifestation is characterized by progressive impairment of memory and cognition, mainly produced by synaptic dysfunction and neuronal loss. This fatal neurodegenerative disease is a matter of great interest because since its first description in 1906 by the psychiatrist A. Alzheimer the AD cases doesn’t stop to increase and more than 90% of disease arise sporadically. Cerebral accumulation of misfofded protein aggregates composed of amyloid b (Ab) proteins and hyperphosphorylated tau protein have been associated to the disease. In the past decade, there has been renewed interest in the possibility that the proteins causing neurodegenerative disorders are all prions. Recently, the origin of the disease, described until now as linked to aging, was re-evaluated by S. Prusiner (Nobel Prize). In animal models he has shown that, when the neurodegenerative process had been started, it propagates over all the brain, by a prion-like mechanism – prion is the responsible agent of Transmissible Spongiform Encephalopathy (TSE) such as Creutzfeldt-Jacob Disease (CJD).


The misfolding and aggregation mechanisms and structural intermediates are very similar in both AD and TSE. The starting point would be a normal protein, PrPC (Cellular Prion) for TSE and APP (Amyloid Precursor Protein) for AD, which would be converted into pathological misfolded proteins (MFP): PrPSc (scrapie Prion) and Ab protein respectively. These MFP would be then implicated in a process of selfaggregation, leading to the formation of amyloid plaques in the brain. Moreover the mechanism of aggregation follows the same seeding-nucleation process.


Several studies in animal models had shown that:


1 For TSE, the PrPSc aggregates generated by this process were infectious.


2 Ab deposition can be induced by injection of AD brain extracts into animals which without exposure to this material will never develop brain alterations.


3 The transfusion of blood from mice with amyloid plaques in brain accelerates the neuro-degenerative phenomenon and the memory loss in two different models of healthy transgenic mice.


In conclusion, questions on the infectivity of Ab protein in Alzheimer’s disease and the possible secondary transmission by blood transfusion are posed.






P-382


REMOVAL OF EXOGENOUS PRION INFECTIVITY IN LEUCOREDUCED RED BLOOD CELLS UNIT BY P-CAPTTM PRION REMOVAL FILTER


Lescoutra N1, Sumian C1, Culeux A1, Durand V2, Deslys JP2 and Comoy EE2 1MacoPharma, Fontenay-aux-Roses, France 2CEA, Prion Research Group, DSV/ IMETI/SEPIA, Fontenay-aux-Roses, France


Background: Five cases of variant Creutzfeldt-Jakob Disease (vCJD) infections were probably linked to infusion of contaminated blood components, turning to real the inter-human transmissibility of this prion disease from asymptomatic carriers. Corresponding preventive policies are currently limited to exclusion from blood donation, but also take advantage of leucoreduction initially implemented against leucotropic viruses. In the absence of available antemortem diagnostic tests, the updated prevalence of silent vCJD infections (1/2000 in the UK) urges the necessity to enforce blood safety with more efficient active measures able to remove remaining infectivity.


Aims: Several affinity resins were proved to experimentally reduce high levels of brain-spiked infectivity from human leucoreduced red blood cell concentrates (L-RBC). One was integrated in a device adapted to field constraints (volumes, duration) of human transfusion. We aimed here to assess the ability of the final device, in its real conditions of use, i.e. the real conditions of filtration with human leucoreduced red cell concentrates (L-RBC), to remove infectivity from human L-RBC unit spiked with scrapie-infected hamster brain.


Methods: A standardized method for preparation of clarified brain homogenate from 263 K infected hamsters, allowing elimination of large aggregates of PrPres without modification of apparent infectivity, was selected for spiking human L-RBC unit. Filtration by gravity, according to the manufacturer’s recommendations, of a 0.0001% spiked L-RBC unit was carried out on day 1 at room temperature. Pre- and post- blood filtration sample aliquots were removed for infectivity studies (intracerebral inoculation of hamsters). Results: Incubation periods of recipient animals suggest around 3 log10 removal of brain-derived prion infectivity by filtration through the P-Capt[TRADEMARK].


Conclusion: On brain-derived spiked infectivity, the P-Capt[TRADEMARK] filter provided similar performances as columns used for initial proof-of-concept studies (Gregori et al., Lancet 2006), suggesting an appropriate scale-up to efficiently remove infectivity from an individual human blood bag. According to the ability of resin to completely remove apparent endogenous infectivity from hamster leucoreduced blood, the implementation of such a filter, now commercially available, might seriously improve blood safety towards prion.






P-383


UPDATE ON THE ABILITY OF THE PRION CAPTURE FILTER, P-CAPTTM, TO DELAY ONSET OF AN ORIGINAL MYELOPATHIC DISEASE OBSERVED IN PRIMATES EXPOSED TO PRION INFECTED BLOOD PRODUCTS


Lescoutra N1, Jaffre N2, Culeux A1, Sumian C1, Durand V2, Mikol JP2, Luccantoni S2, Deslys JP2 and Comoy EE2


1MacoPharma, Fontenay-aux-Roses, France 2CEA, Prion Research Group, DSV/ IMETI/SEPIA, Fontenay-aux-Roses, France


Background: In the United Kingdom, the recent report of four human cases of variant of Creutzfeldt-Jakob disease (vCJD) through transfusion has justified the implementation of measures to secure blood and blood products towards prions. Leucoreduction, implemented against blood-borne viruses, is not sufficient to remove the entire prion blood infectivity, halved between white cells and plasma. In absence of antemortem diagnostic tests, several devices, including P-Capt[TRADEMARK] filter, were designed to remove prions. This filter incorporates an affinity resin specific for PrP, which has already demonstrated its efficiency in removing both exogenous and endogenous prion infectivity in the experimental model of hamster infected with the experimental 263 K strain. The ability of the P-Capt [TRADEMARK] filter was also previously assessed with human L-RBC artificially contaminated with 263 K clarified brain extracts and demonstrated comparable efficiency.


Aims: We aimed to complete the evaluation of the P-Capt[TRADEMARK] filter with blood-borne infectivity in the cynomolgus macaque considered as an utmost relevant model for the investigation of human prion diseases. Methods: Two independent experiments were performed 1 year apart. First, five donor primates were intravenously (iv) inoculated with high amounts of clarified brain homogenate from a BSE-infected primate to maximize their blood infectivity. At the onset of first clinical signs, their blood was drawn and pooled to reach a volume equivalent to a human blood donation. After whole blood leucoreduction, Red Blood Cell Concentrate (L-RBC) was prepared following routine blood human procedures. L-RBC was suspended in plasma according to conditions used for pediatric transfusion in the UK. Twenty-seven milliliters were transfused to two or three recipient primates prior or after P-Capt[TRADEMARK] filtration respectively. In the second experiment designed for the evaluation of a combined filter for leucoreduction and prion removal, the same scheme was applied with RBC (suspended in Sag-M) issued from six animals intravenously infected with clarified brain homogenate from a vCJD-infected primate.


Results: In the BSE experiment, both primates injected with L-RBC before filtration developed an original neurological disease 30 and 31 months post inoculation and died 2 months later. This original neurodegenerative disease is described by E. Comoy et al. as an atypical form of prion disease. Conversely, all the three animals transfused with P-Capt[TRADEMARK] filtrated L-RBC still remained asymptomatic 54 months post transfusion. In the v-CJD experiment, first clinical signs evocative of the myelopathic syndrome were detected in both primates before filtration 20– 27 months post inoculation. One of them was subject to euthanasia 42 mpi, and pathological examination confirmed the occurrence of the myelopathic syndrome. The others animals are still asymptomatic.


Conclusions: The P-Capt was shown to be able to retain classical prion strains. Here in two independent experiments, we demonstrate that this filter is also able to retain atypical strains recently identified in primates after exposition to human blood products.




P-384


CONTAMINATED BLOOD PRODUCTS INDUCE AN ATYPICAL PRION DISEASE IN PRIMATES IN THE ABSENCE OF DETECTABLE ABNORMAL PRION PROTEIN


Comoy EEC1, Jaffre N1, Mikol J1, Durand V1, Luccantoni S1, Correia E1, Jas-Duval C2, Cheval J3, Eloit M4 and Deslys JP1


1Atomic Energy Commission, Fontenay-aux-Roses, France 2EFS, Lille, France 3Pathoquest, Paris, France 4Pasteur Institute, Paris, France


Background: Concerns about the blood-borne risk of prion infection have been confirmed by the occurrence in the UK of four transfusion-related infections of vCJD (variant Creutzfeldt-Jakob disease), and an apparently silent infection in an hemophiliac patient. Asymptomatic incubation periods in prion diseases can extend over decades in humans. Several parameters, including factors driving blood infectivity, remain poorly understand.


Aims: We used a validated non-human primate model of prion disease to evaluate the transfusional risk linked to v-CJD in human.


Methods: Cynomolgus macaques were inoculated with brain or blood specimens from vCJD infected humans and vCJD or BSE-infected monkeys. Neuropathological and biochemical findings were obtained using current methods used for human patients.


Results: Six out of 12 primates exposed to human or macaque blood-derived components exhibited after a long silent incubation period exceeding 5 years an original neurological disease (myelopathy) previously not described either in humans or primates, and which is devoid of the classical clinical and lesional features of prion disease (front leg paresis in the absence of central involvement, lesions concentrated in anterior horns of lower cervical cord, with no spongiosis or inflammation), while the nine brain-inoculated donor animals and one transfused animal exhibited the classical vCJD pattern, and the five other primates exposed to blood-derived components remain asymptomatic. No abnormal prion protein (PrPres) was detected by standard tests in use for human prion diagnosis. No alternative cause has been found in an exhaustive search for metabolic, endocrine, toxic, nutritional, vascular and infectious etiologies, including a search for pathogen genotypes (‘deep sequencing’). In secondary transmission experiments in primates, after shorter incubation periods (<2 a="" accumulation.="" and="" cord="" disease="" div="" induced="" inoculation="" intracerebral="" myelopathic="" of="" plasma="" prion="" prpres="" same="" spinal="" spongiosis="" syndrome="" the="" transfusion="" transmitted="" typical="" whereas="" with="" years="">

Conclusion: We describe a new neurological syndrome in monkeys exposed to various vCJD/BSE-infected blood components. Secondary transmission in primates confirm first the transmissibility of this myelopathy, and second its prion origin which could not be diagnosed as such in the first recipients. This myelopathy might be compared under some aspects to certain forms of human lower motor neuron diseases including neuromyelitis optica, the flail arm syndrome of ALS and the recently described FOSMN. Similar human infections, were they to occur, would not be identified as a prion disease by current diagnostic investigations.








Tuesday, May 21, 2013


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Sunday, May 19, 2013


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Tuesday, March 5, 2013


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7:2, 99–108; March/April 2013; © 2013 Landes Bioscience









Sunday, February 10, 2013


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Tuesday, May 7, 2013


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TSS

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