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
IS ALZHEIMER’S DISEASE A PRION DISEASE? the possible secondary transmission
by blood transfusion are posed
Sunday, May 19, 2013
CJD BLOOD SCREENING, DONORS, AND SILENT CARRIERS House of Commons Written
Answers 16 May 2013
Monday, May 6, 2013
Warning of mad cow disease threat to blood transfusions
Tuesday, April 30, 2013
Mad cow infected blood 'to kill 1,000’
Friday, June 29, 2012
Highly Efficient Prion Transmission by Blood Transfusion
Tuesday, March 5, 2013
Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening
of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)
FDA believes current regulation protects the public from BSE but reopens
comment period due to new studies
Tuesday, March 05, 2013
A closer look at prion strains Characterization and important implications
Prion
7:2, 99–108; March/April 2013; © 2013 Landes Bioscience
Sunday, February 10, 2013
Creutzfeldt-Jakob disease (CJD) biannual update (February 2013) Infection
report/CJD
Tuesday, May 7, 2013
Proteinopathies, a core concept for understanding and ultimately treating
degenerative disorders?
TSS
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.