From: TSS ()
Subject: SEAC Position statement on TSE infectivity in blood
Date: August 2, 2006 at 6:37 am PST
SEAC
Position Statement
--------------------------------------------------------------------------------
Position statement on TSE infectivity in blood
Issue
1. 1. The UK blood services and Department of Health (DH) asked SEAC to consider data on the nature of transmissible spongiform encephalopathy (TSE) infectivity in blood and the implications for transmission of variant Creutzfeldt-Jakob disease (vCJD) via transfusion of blood products. The committee considered four specific issues:
(i) the level of TSE infectivity in whole blood and the distribution of infectivity amongst individual components of blood,
(ii) the change in the level of TSE infectivity in blood over the course of the incubation period of disease,
(iii) the relative efficiencies of the intracranial (ic) and intravenous (iv) routes of inoculation,
(iv) the dose-response relationship for TSE infection.
Background
2. Blood has been shown to carry TSE infectivity in a number of different animal models 1-4. Three cases of probable vCJD transmission via transfusion of non-leucodepleted red blood cells provide strong evidence that blood from humans infected with vCJD can carry the infectious agent during the pre-clinical stage of the disease 5-7.
3. Precautionary measures, including leucodepletion and importation of fresh frozen plasma for children, have been implemented by the UK blood services to reduce the risk of vCJD transmission via blood transfusion. Additional blood processing technologies that may further reduce transmission risks are under consideration. Assessment of the potential effectiveness of new technologies relies on assumptions about the nature of the infectivity in blood, particularly the level and distribution of vCJD infectivity in blood components. However, there is much uncertainty about the nature, level and distribution of infectivity in blood. An assessment produced by Det Norske Veritas Consulting (DNV) and reviewed by SEAC provides a working model for the level of vCJD infectivity in blood and the distribution of infectivity between blood components 8.
4. At SEAC 92, SEAC reassessed some of the assumptions in the DNV risk assessment by consideration of recent published literature and unpublished data presented by a number of researchers 9-13. Many of the available data were derived from animal studies that have used prion strains, inocula and routes of administration that may not be directly applicable to the human blood transfusion situation. Most of the data are from studies of infectivity in hamster blood infected with hamster scrapie 3,10,13,14 and mice infected with mouse adapted vCJD 2. Many of the hamster studies have not yet been published and therefore, have not been subject to the usual peer review process. Extrapolation of data from studies of hamster scrapie to vCJD is complicated by differences in the pathogenesis of these diseases, particularly the low level of lymphoreticular system (LRS) involvement in the pathogenesis of hamster scrapie in contrast to vCJD. Limited data, that may be more relevant, are available from ongoing studies of the infectivity in the blood of sheep experimentally infected with BSE or scrapie as the pathogenesis of these diseases involve the LRS in this model 11.
Level of TSE infectivity in whole blood
5. The levels of infectivity reported in rodent studies to examine the infectivity in blood of animals with TSEs vary widely, ranging from about one to 300 infectious doses*(ID)/mL of blood. One large unpublished study 10 involving a series of experiments to measure the infectivity in samples of pooled blood from large groups of hamsters with hamster scrapie suggests a mean level of infectivity of around 10 ID/mL of blood (range of two to 24 ID/mL of blood). In a published study, levels of mouse adapted vCJD infectivity within this lower range were found in blood components from mice at late pre-clinical or clinical stages of infection 2. There are no data on the infectivity in the blood of humans with vCJD to assess the relevance of these data to humans.
Origin of blood infectivity
6. The source of infectivity in blood is not understood. Unpublished comparisons of the infectivity in blood from intact and splenectomised hamsters suggest that the spleen is not the source of infectivity in blood 10. Unpublished comparisons 10 of the rate of increase of infectivity in pooled blood and brain from infected hamsters during the incubation period of hamster scrapie suggest that it is not the result of leakage from the central nervous system (CNS) into the blood supply 10. However, a single published study that measured abnormal prion protein (PrPSc) in the buffy coat (white blood cells and platelets) from single hamsters infected with hamster scrapie suggests that PrPSc concentrations in blood are bimodal with a peak in the pre-clinical phase from peripheral replication in the spleen and other lymphoid tissues, followed by a larger rise in PrPSc concentrations leading into the clinical stage of the disease from leakage from the CNS 13.
Distribution of infectivity in blood components
7. Published and unpublished data from studies of the infectivity in components of blood from hamsters with hamster scrapie show that around one half of the infectivity in blood can be removed by depleting blood of white blood cells 3, and that the infectivity associated with the white blood cells can be substantially depleted by extensive washing 10. In addition, infectivity is not, or is minimally, associated with platelets 14 or red blood cells 10. These data suggest, at least in this model of TSE infection, that infectivity may be distributed equally between plasma and white blood cells but is weakly bound to white blood cells. Data from published experiments to measure mouse adapted vCJD infectivity in components of blood taken at the late pre-clinical or clinical stages of disease also suggest that infectivity is principally associated with plasma and white blood cells, minimally associated with red blood cells but that there may be some association with platelets 2. The buffy coat from sheep with scrapie or BSE has also been shown to transmit infection by transfusion to healthy recipient sheep 1,11. It is possible that there are inter-species and inter-strain differences in the distribution of TSE infectivity in blood components. Therefore, additional research to examine the infectivity in blood components, particularly from models using TSE strains closely related to vCJD, will allow assessment of the relevance of these data to humans infected with vCJD.
Change in infectivity during the incubation period
8. A number of studies in animals have examined the level of infectivity in blood during both the pre-clinical and clinical stages of TSE infection 2,9,11. An unpublished study 10 examined the infectivity in the blood of hamsters after ic inoculation with hamster scrapie at a number of time points during the preclinical stage of infection. Infectivity was first detected at the mid-point of the incubation period with the level of infectivity increasing linearly towards the clinical stage of infection. Extrapolation of these data suggests infectivity may first appear in blood at around a third of the way into the incubation period. Similar findings were obtained when the experiment was repeated using oral inoculation. Although the relationship between PrPSc and infectivity is unclear, PrPSc concentrations in the blood of hamsters infected with hamster scrapie show a bimodal profile (as described in paragraph 7) 13. Studies of mouse adapted vCJD 2,9 and sheep infected with scrapie or BSE 1,11 only examined the level of infectivity at one point during the preclinical stage of infection but show that blood is infectious during the second half of the incubation period. Two cases of probable blood transfusion associated transmission of vCJD from blood donors 20 months 5 and 3.5 years 7 prior to the onset of disease have been identified, indicating that human blood can be infectious in the preclinical phase. More extensive data, particularly from models using TSE strains closely related to vCJD, will inform on the relevance of the findings in the hamster scrapie model to changes in infectivity in the incubation period of vCJD in humans.
Relative efficiency of the ic and iv routes of transmission
9. The efficiency of transmission varies depending on the route of administration, host, TSE strain, source of inoculum and how it is prepared. Most measurements of TSE infectivity are derived from bioassays using the ic route of administration. Since the efficiencies of the ic and iv routes of transmission may not be equivalent, the infectivity of an inoculum measured by the ic route may not reflect the infectivity of the same inoculum administered by the iv route, this latter route being the most relevant to blood transfusion. A small number of studies using different animal models have compared the infectivity of brain homogenate or purified blood components administered by the ic or iv routes. These studies suggest that the efficiency of transmission by the iv route is between 10% and 100% of the efficiency of ic route 2,4,9,14,15. One unpublished study 10, comparing the efficiency of iv transfusion of intact whole blood and ic inoculation of sonicated whole blood from hamsters with hamster scrapie showed the iv route to be considerably less efficient than suggested by this range. In addition, a published study 2 showed that mouse adapted vCJD could be transmitted equally efficiently from inoculation of buffy coat from infected animals by the ic or iv routes but the transmission efficiency from inoculation of plasma was lower by the iv compared with the ic route. These studies suggest that the form of inoculum may strongly influence the relative transmission efficiencies of inoculation by different routes.
Dose-response relationship
10. Evidence from animal studies 10 suggests that TSE infectivity is quantal in nature. An infectious dose diluted by distribution to a number of individuals reduces the risk of transmission to an individual. However, at the population level, one of the exposed individuals would be still be expected to become infected. Higher doses split between individuals would lead to more than one infection. The implication of this relationship between dose and probability of infection for strategies to reduce the public health risks in relation to blood transfusion is that pooling blood to dilute infectivity does not decrease the risks to public health. Indeed, depending on the dose, pooling is likely to increase the risks to public health. Strategies to remove or inactivate infectivity in blood would reduce the risks of transmission to both the individual and at the population level.
Conclusions
11. The available data show that blood is infectious during the preclinical stage of vCJD. Although the precise time in the incubation period of vCJD at which blood becomes infectious is unclear, data from animal models suggests it may be infectious from at least, if not before, the middle of the incubation period. The source of infectivity in blood is not understood. Data from rodent studies suggests that infectivity in whole blood is around 10 ID/mL and that it mostly resides in the plasma and white blood cell components with infectivity associated with white blood cells substantially depleted by extensive washing. However, additional information from other animal models is required to assess whether these findings may be closely representative of vCJD infectivity in human blood. It is clear that an infectious dose in blood can be disseminated but not diluted by distribution to a large number of recipients. Consequently, pooling of potentially infectious material, or in other ways disseminating infectious material between a number of recipients, will not reduce the number of people infected, and is likely to increase the number of people infected.
SEAC
July 2006
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References
1. Hunter et al. (2002) Transmission of prion diseases by blood transfusion. J. Gen. Virol. 83, 2897-2905.
2. Cervenakova et al. (2003) Similar levels of infectivity in the blood of mice infected with human-derived vCJD and GSS strains of transmissible spongiform encephalopathy. Transfusion. 43, 1687-1694.
3. Gregori et al. (2004) Effectiveness of leucodepletion for removal of infectivity of transmissible spongiform encephalopathies from blood. Lancet. 364, 529-531.
4. Hertzog et al. (2004) Tissue distribution of bovine spongiform encephalopathy agent in primates after intravenous or oral infection. Lancet. 363, 422-428.
5. Health protection Agency (2006): New case of variant CJD associated with blood transfusion.
6. Peden et al. (2004) Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet. 364, 527-529
7. Llewelyn et al. (2004) Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet. 363, 411-412.
8. DNV Consulting (2003) Risk assessment of exposure to vCJD infectivity in blood and blood products.
9. Unpublished data from the Jerome H. Holland Laboratory for Biomedical Sciences, American Red Cross, Maryland, USA presented by Dr L Cervenakova.
10. Unpublished data from the VA Medical Center, University of Maryland, Baltimore, USA presented by Dr R Rohwer.
11. Unpublished data from the Institute for Animal Health, Compton, Berkshire, UK presented by Professor J. Manson.
12. Unpublished data from the Laboratory for Prion Pathogenesis, Atomic Energy Commission, Service de Neurovirologie, Cedex, France presented by Professor C Lasmézas.
13. Saá et al. (2006) Presymptomatic detection of prions in blood. Science. 313, 92-94.
14. Holada et al. (2002) Scrapie infectivity in hamster blood is not associated with platelets. J. Virol. 76, 4649-4650.
15. Kimberlin (1991) An overview of bovine spongiform encephalopathy. Dev. Biol. Stand. 75, 75-82.
16. Brown et al. (1998) The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy. Transfusion 38, 810-816.
Page updated: 1st August 2006
http://www.seac.gov.uk/statements/statement0806.htm
Subject: FDA mad cow nvCJD 'only' blood recalls 2ND WEEK JULY 2006
Date: July 16, 2006 at 6:57 am PST
PRODUCT
a) Red Blood Cells Leukocytes Reduced, Recall # B-1550-6;
b) Fresh Frozen Plasma, Recall # B-1551-6
CODE
a) and b) Unit 2395371
RECALLING FIRM/MANUFACTURER
South Texas Blood and Tissue Center, San Antonio, TX, by fax on August 20, 2003. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
TX
______________________________
PRODUCT
a) Red Blood Cells Leukocytes Reduced, Recall # B-1552-6;
b) Platelets, Recall # B-1553-6;
c) Fresh Frozen Plasma, Recall # B-1554-6
CODE
a), b) and c) Unit 2438702
RECALLING FIRM/MANUFACTURER
South Texas Blood and Tissue Center, San Antonio, TX, by fax on May 29, 2003. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
3 units
DISTRIBUTION
TX
______________________________
PRODUCT
a) Red Blood Cells Leukocytes Reduced, Recall # B-1555-6;
b) Fresh Frozen Plasma, Recall # B-1556-6
CODE
a) and b) Unit 2454970
RECALLING FIRM/MANUFACTURER
South Texas Blood and Tissue Center, San Antonio, TX, by fax on July 23 and December 11. 2003. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
TX
______________________________
PRODUCT
a) Red Blood Cells, Recall # B-1494-6
b) Cryoprecipitated AHF, Recall # B-1495-6
CODE
a) and b) Unit 5013100
RECALLING FIRM/MANUFACTURER
Walter L. Shepeard Community Blood Center, Inc., Augusta, GA, by fax on May 17, 2005. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
GA
______________________________
PRODUCT
Source Plasma, Recall # B-1450-6
CODE
Unit numbers ST0824313 and ST0824764
RECALLING FIRM/MANUFACTURER
Stillwater Plasma Center LLC, Stillwater, OK, by fax on November 21, 2003. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor whose suitability pertaining to risk factors for Creutzfeldt-Jakob Disease (vCJD) was not adequately determined, were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
UK
______________________________
PRODUCT
Plasma Frozen, Recall # B-1422-6;
Recovered Plasma, Recall # B-1423-6
CODE
a) Unit 03E42218;
b) Unit 03E38153
RECALLING FIRM/MANUFACTURER
American Red Cross Blood Services, Atlanta, GA, by telephone, e-mail or letter on February 20 or 21, 2004. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
GA and Switzerland
______________________________
PRODUCT
a) Red Blood Cells Leukocytes Reduced, Recall # B-1374-6;
b) Recovered Plasma, Recall # B-1375-6
CODE
a) and b) unit 2453906
RECALLING FIRM/MANUFACTURER
South Texas Blood and Tissue Center, San Antonio, TX, by fax on October 31 and November 5, 2003. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
TX and Austria
______________________________
PRODUCT
Source Plasma. Recall # B-1295-6
CODE
Units: NG0046551, NG0045950
RECALLING FIRM/MANUFACTURER
DCI Biologicals Nacogdoches LLC, Nacogdoches, TX, by telephone and fax on December 20, 2002, Firm initiated recall is complete.
REASON
Blood products, collected from a donor who did not answer the questions on the new variant Creutzfeldt-Jacob disease (nvCJD) questionnaire appropriately, were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
KY
______________________________
PRODUCT
Source Plasma. Recall # B-1296-6
CODE
Unit: NG 0044520
RECALLING FIRM/MANUFACTURER
DCI Biologicals Nacogdoches LLC, Nacogdoches, TX, by telephone and fax on December 12, 2002. Firm initiated recall is complete.
REASON
Blood product, collected from a donor who did not answer the questions on the new variant Creutzfeldt-Jacob disease (nvCJD) questionnaire, was distributed.
VOLUME OF PRODUCT IN COMMERCE
1 unit
DISTRIBUTION
KY
______________________________
PRODUCT
Source Plasma. Recall # B-1297-6
CODE
Units: NG0042874, NG0043139, NG0043312, NG0043618, NG0043797, NG0044020, NG0044209, NG0044507, NG0044718, NG0044977, NG0045161, NG0045412, NG0045555
RECALLING FIRM/MANUFACTURER
DCI Biologicals Nacogdoches LLC, Nacogdoches, TX, by telephone and fax on December 20, 2002. Firm initiated recall is complete.
REASON
Blood products, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
13 units
DISTRIBUTION
KY
______________________________
PRODUCT
Source Plasma, Recall # B-1298-6
CODE
Units: NG 0046823, NG 0046671, NG 0045205, NG 0044635, NG 0043095, NG 0042525, NG 0042341
RECALLING FIRM/MANUFACTURER
DCI Biologicals Nacogdoches LLC, Nacogdoches, TX, by telephone and fax on December 20, 2002. Firm initiated recall is complete.
REASON
Blood products, collected from a donor who answered questions on the variant Creutzfeldt-Jacob disease (vCJD) questionnaire inappropriately, were distributed.
VOLUME OF PRODUCT IN COMMERCE
7 units
DISTRIBUTION
KY
______________________________
PRODUCT
Recovered Plasma, Recall # B-1299-6
CODE
Unit: 4357117
RECALLING FIRM/MANUFACTURER
Department of the Navy, Naval Medical Center, San Diego, CA, by fax and letter on September 25, 2003. Firm initiated recall is complete.
REASON
Blood product, collected from a donor considered to be at risk of exposure to Creutzfeldt-Jacob Disease (CJD), was distributed.
VOLUME OF PRODUCT IN COMMERCE
1 unit
DISTRIBUTION
Germany
END OF ENFORCEMENT REPORT FOR July 12, 2006
###
http://www.fda.gov/bbs/topics/enforce/2006/ENF00960.html
CJD WATCH MESSAGE BOARD
TSS
FDA mad cow nvCJD 'only' blood recalls 1ST WEEK JULY
Fri Jul 7, 2006 09:37
70.110.83.160
FDA mad cow nvCJD 'only' blood recalls 1ST WEEK JULY
PRODUCT
a) Red Blood Cells Leukocytes Reduced, Recall # B-1379-6;
b) Platelets, Recall # B-1380-6;
c) Fresh Frozen Plasma, Recall # 1381-6;
d) Recovered Plasma, Recall # B-1382-6
CODE
a) Unit numbers: 2343106, 2377779, and 2403533;
b) and c) Unit numbers: 2377779;
d) Unit numbers: 2343106 and 2403533
RECALLING FIRM/MANUFACTURER
South Texas Blood and Tissue Center, San Antonio, TX, by facsimile on June 12, 2003. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
7 units
DISTRIBUTION
TX and Austria
______________________________
PRODUCT
a) Red Blood Cells Leukocytes Reduced, Recall # B-1467-6;
b) Recovered Plasma, Recall # B-1468-6
CODE
a) and b) Unit numbers: 2329380
RECALLING FIRM/MANUFACTURER
South Texas Blood and Tissue Center, San Antonio, TX, by facsimile on May 8, 2003. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
TX and Switzerland
______________________________
PRODUCT
a) Red Blood Cells Leukocytes Reduced, Recall # B-1479-6;
b) Cryoprecipitated AHF, Recall # B-1480-6;
c) Recovered Plasma, Recall # B-1481-6
CODE
a), b), and c) Unit numbers: 2383280
RECALLING FIRM/MANUFACTURER
South Texas Blood and Tissue Center, San Antonio, TX, by facsimile on July 23 and 29, 2004. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
3 units
DISTRIBUTION
TX and Switzerland
______________________________
PRODUCT
a) Red Blood Cells Leukocytes Reduced, Recall # B-1482-6;
b) Fresh Frozen Plasma, Recall # B-1483-6
CODE
a) and b) Unit number: 2501452
RECALLING FIRM/MANUFACTURER
South Texas Blood and Tissue Center, San Antonio, TX, by facsimile on October 5, 2004. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
2 units
DISTRIBUTION
TX and NY
______________________________
PRODUCT
a) Red Blood Cells Leukocytes Reduced, Recall # B-1484-6;
b) Plasma Cryoprecipitated Reduced, Recall # B-1485-6;
c) Recovered Plasma, Recall # B-1486-6
CODE
a) and c) Unit number: 2554077;
b) Unit number: 2415708
RECALLING FIRM/MANUFACTURER
South Texas Blood and Tissue Center, San Antonio, TX, by facsimile on August 13, 2004. Firm initiated recall is complete.
REASON
Blood products, which were collected from a donor who may be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE
3 units
DISTRIBUTION
TX and Austria
_____________________________________
END OF ENFORCEMENT REPORT FOR July 5, 2006
###
http://www.fda.gov/bbs/topics/enforce/2006/ENF00959.html
with new atypical TSE in the bovine, in the sheep, goat, and humans, and the fact that the new BASE TSE in cattle being very very similar to sporadic CJD, rather than the nvCJD, the fact that now science showing the TSE agent of the atypical cattle in Japan showing infectivity other than CNS tissue, the fact that the latest Texas mad cow and the recent Alabama mad cow both being of the atypical strain, it would seem prudent to include all human TSE in the blood ban, in my opinion. ...
TSS
CJD WATCH MESSAGE BOARD
TSS
Prion infections, blood and transfusions Aguzzi and Glatzel
Sat Jul 8, 2006 12:18
68.238.108.213
Prion infections, blood and transfusions
Adriano Aguzzi* and Markus Glatzel
Prion infections lead to invariably fatal diseases of the CNS, including
Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform
encephalopathy (BSE), and scrapie in sheep. There have been hundreds
of instances in which prions have been transmitted iatrogenically among
humans, usually through neurosurgical procedures or administration of
pituitary tissue extracts. Prions have not generally been regarded as bloodborne
infectious agents, and case-control studies have failed to identify
CJD in transfusion recipients. Previous understanding was, however,
questioned by reports of prion infections in three recipients of blood
donated by individuals who subsequently developed variant CJD. On
reflection, hematogenic prion transmission does not come as a surprise, as
involvement of extracerebral compartments such as lymphoid organs and
skeletal muscle is common in most prion infections, and prions have been
recovered from the blood of rodents and sheep. Novel diagnostic strategies,
which might include the use of surrogate markers of prion infection, along
with prion removal strategies, might help to control the risk of iatrogenic
prion spread through blood transfusions. ...
snip...
INTRODUCTION
Prion diseases, also termed transmissible
SPONGIFORM ENCEPHALOPATHIES, constitute
a group of neurodegenerative conditions that
are transmissible within and between mammalian
species. A characteristic of these diseases is
the accumulation of a misfolded prion protein,
PrPSc, which is a post-translationally modified
form of the host-encoded prion protein (PrPC).
The processes underlying PrPSc formation
remain enigmatic, but there is little doubt that
a conformer of PrPC, which might exist in an
oligomeric form,1 is identical to the infectious
entity.2 Prions damage the brain by transmitting
toxic signals to cells expressing PrPC.3
Although genetic evidence has been taken
to indicate that human prion diseases have
been with us since prehistoric times,4 the first
documented cases of Creutzfeldt-Jakob disease
(CJD) date back only 85 years.5-7 Since then, it
has become obvious that human prion diseases
have three distinct etiologies: they can arise in the
absence of any documented exposure to infectious
prions as sporadic CJD (sCJD), as an autosomal
dominantly inherited disease in the case
of genetic, or familial, CJD (gCJD/fCJD), or as
an acquired condition in the case of IATROGENIC
and variant CJD (iCJD, vCJD), or kuru, which
resulted from cannibalism.8
Some prion diseases that occur in animals
might have been recognized several centuries
ago, as suggested by early descriptions of sheep
diseases that seem to correspond to scrapie.
Most prion diseases affecting animals, however,
were discovered relatively recently.6 A transmissible
spongiform encephalopathy affecting
cattle (bovine spongiform encephalopathy,
or BSE) has caused a massive epidemic in
European countries, affecting around 2 million
animals.9 Epidemiological, biochemical, neuropathological
and transmission studies have
substantiated the concern that BSE prions might
have crossed the species barrier between cattle
and humans, resulting in a novel form of human
prion disease, vCJD.10-13 During 1996-2001, the
incidence of vCJD in the UK rose year upon year,
evoking fears of a large upcoming epidemic.
Since 2001, however, the incidence of vCJD in
the UK appears to have been stabilizing, indicating
that the extent of the epidemic might be
limited.14 As might be expected for in frequent
stochastic events, the numbers of new cases of
vCJD fluctuate from year to year. For example,
data available on the web page of the National
CJD Surveillance Unit15 show that the number
of onsets of vCJD was higher in 2004 than it was
in 2003, but this is not necessarily indicative of
an upward trend.
It must be assumed that a number of asymptomatic
carriers of vCJD exist in human populations
that have been exposed to BSE. The
existence of such a chronic carrier state is a
logical and unavoidable consequence of the
long incubation time of prion diseases, which
is typically in the order of several years and-
in the case of oral exposure to prions-can
reach several decades. Consequently, anybody
who has contracted the infection but has not
developed clinical signs and symptoms might
be consider ed a carrier. Some of these carriers
are likely be 'preclinical', and will proceed,
in due course, to the development of disease.
Alternatively, it is conceivable that the carrier
state can persist for an indefinite period of
time, in which case infected individuals could
be regarded as 'permanent asymptomatic
(sub clinical) carriers'. Studies performed in
rodents indicate that the permanent subclinical
carrier state might be a common phenomenon,
such as occurs when immune deficient mice
are exposed to prions.16 Unlinked anonymous
screens for hallmarks of prion infection in
archival tissues have suggested that the prevalence
of individuals with sub clinical vCJD might
be higher than previously antici pated, and could
reach 237 cases per million individuals.17
The recent discovery of transmission of vCJD
via blood in three individuals indicates with
near certainty that blood-borne prion transmission,
in conjunction with an unknown
prevalence of vCJD-infected carriers, leads
to secondary transmission of host-adapted
prions.18 Consequently, the vCJD epidemic
might be prolonged, or, in the worst-case
scenario, vCJD be rendered endemic and selfsustained.
In this article, we review how prions
could act as blood-borne infectious agents, and
consider strategies aimed at minimizing the risk
of secondary trans mission of prion diseases.
TRANSMISSION OF PRION DISEASES
IN HUMANS
The cause of most human prion diseases is
unknown. In the case of sCJD, the term 'sporadic'
is used as a euphemism, meaning that we have
no idea about the origin of this form of CJD. By
contrast, gCJD always segregates within families
with mutations in the gene encoding the prion
protein (PRNP), suggesting that these mutations
are causally involved in disease pathogenesis. As
no families have been described in which gCJD
segregates with mutations in genes other than
PRNP, it has been difficult to use human genetics
to understand the pathogenesis of prion diseases.
The discovery of PRNP mutations in gCJD has
led to the proposal that at least some cases of
sCJD might be due to somatic PRNP mutations
analogous to those found in the germline of
gCJD patients. It is equally possible, however,
that some of the cases of alleged sCJD derive
from hitherto unrecognized infectious causes.
In apparent agreement with the 'intrinsic'
origin of sCJD, which accounts for more than
90% of all human prion diseases, epidemiological
studies were not able to identify a
conclusive link between this form of CJD and
external risk factors.19 This fact is reflected in
the pathological and biochemical features of
these diseases. Although low levels of PrPSc and
prion infectivity can be demonstrated in peripheral
sites such as lymphoid organs or skeletal
muscle,20,21 the highest levels of PrPSc and prion
infectivity appear to occur in the CNS. These
facts might account, at least in part, for the lack
of evidence of sCJD transmission by labile or
stable blood products.22 Indeed, several retrospective
studies have failed to identify blood
transfusion or exposure to plasma products as
risk factors for the development of sCJD,19 and
prion diseases appear to be exceedingly rare
in hemophiliacs, a group of patients that is at
particularly high risk of contracting emerging
blood-borne infectious diseases. Although these
studies cannot exclude the possibility that transmission
of sCJD might have occurred through
blood transfusions in rare cases, and despite
the fact that the etiology of sCJD is unclear,
it would appear that transmission of sCJD by
trans fusion of blood or blood products does
not play a major role in the pathogenesis of this
disease entity.
In the case of acquired prion diseases, however,
the situation is very different. For vCJD, high
levels of prion infectivity and of PrPSc have
been detected in lymphoid organs such as the
appendix and tonsils (Figure 1).23,24 For this
reason, it has been speculated for almost a decade
that vCJD might be associated with a higher risk
of blood-borne transmission than sCJD. It is
important to be cautious, however, as the differences
in the organ tropism of sCJD and vCJD
might be quantitative rather than qualitative, and
PrPSc has been detected in the lymphoid organs
of both vCJD and sCJD patients.21 Initial studies
have failed to detect PrPSc and prion infectivity
in the blood of patients with vCJD, but these
negative data are likely to be attributable to
the lack of sensitivity of the assays available at
the time.23
The recent identification of three indiv iduals
with probable transmission of vCJD via blood
transfusion has provided tragic evidence that vCJD
prions can indeed be transmitted through blood
(Figure 2). On the basis of the epi demiological
and pathogenetic considerations discussed above,
it can only be a matter of time before further
cases of blood-transfusion-associated cases of
vCJD will ensue (Figure 3).
In the first of the cases reported, a patient
received a single unit of non-leukodepleted
erythrocyte concentrate from an individual who
went on to develop vCJD 3.5 years later, and
was therefore likely to have been subclinically
prion-infected at the time of the donation. The
recipient developed vCJD 6.5 years following
the transfusion.25
In the second case, transmission of prion
disease occurred again via a single unit of nonleukodepleted
red-blood-cell concentrate.
The donor developed vCJD 2 years following
blood donation, again raising the possibility
of pre clinical infection at the time of the donation.
18 The recipient died of causes unrelated
to the prion infection 5 years after the transfusion.
Although this individual did not display
overt signs of vCJD, PrPSc could be detected
in lymphoid organs, enforcing the concept of
subclinical prion disease in this individual.
Recently, a third case of blood-borne prion
transmission has been reported.26 In this case,
the incubation time in the recipient was 8 years,
whereas the donor showed vCJD symptoms
20 months following his blood donation.
Until now, sequencing of the PRNP gene
in all individuals who succumbed to vCJD
revealed homozygosity for the sequence 'ATG',
which encodes methionine, at codon 129. In
the general population, only 33% of people are
homozygous for ATG at this codon of PRNP, so
this particular genetic trait, known as the MM
genotype, has been regarded as a risk factor for
vCJD.8 The second identified recipient of prioninfected
blood, however, was heterozygous for
methionine/valine at codon 129 (MV genotype).
The MV genotype is underrepresented in
sporadic and acquired CJD, and has therefore
been considered a protective genetic trait. The
fact that this individual died of a cause unrelated
to prion disease raises the question of whether
MV heterozygotes might develop a permanent
carrier status, in which the prion replicates
within their body but clinical signs are absent
for an indeterminate period of time.
Of course, it would be imprudent to draw
far-reaching conclusions on the basis of three
cases of blood-borne prion infection. We deem
it justified, however, to highlight a number of
surprising details that have become clear on
analysis of these cases.
First, vCJD prions can indeed propagate using
blood as a vector. In the past, this idea has often
been regarded as 'worst-case scenario', 'highly
specula tive', and 'barely a theoretical possibility'.
The wishful thinking of many physicians
involved in blood transfusion has often conjured
up a sense of safety, which, as we regrettably now
know, is unwarranted.
Second, a single unit of vCJD-prion-infected
blood is sufficient to cause transmission of the
disease. This fact is particularly unsettling, as it
can only be taken to signify that the concentration
of ID50 units in blood is relatively high.
One ID50 unit is defined as the infectious
dose sufficient to establish infection in 50% of
recipients; animal experiments indicate that the
amount of prion infectivity needed to reach
one ID50 unit is much higher when prions are
administered intravenously than when they
are inoculated intracerebrally.
Third, blood from preclinically vCJD-infected
patients can be infectious. Although not
un expected, this aspect is particularly worrisome,
as it suggests that preclinical donors
might subjectively not consider themselves at
risk. Consequently, the only way to identify such
donors would be to subject the donation to a
prion screen of satisfactory sensitivity, which is
currently unavailable.
Last, despite all epidemiological evidence to
the contrary, patients who are methionine/valine
heterozygous at codon 129 of the PRNP gene are
susceptible to infection with vCJD prions, which
raises several important questions. Is the virulence
of BSE prions enhanced when passaged
from human to human, as opposed to the
original bovine to human situation? Passaging
experiments of scrapie infectivity between mice
and hamsters indicate that this scenario is highly
plausible.6 Even more importantly, can vCJD
infection of heterozygous individuals establish
a permanent subclinical carrier state? Although
this situation might constitute a best-case
scenario for the infected individuals, it could be
disastrous from an epidemiological viewpoint,
as it might lead to an unrecognized and possibly
self-sustaining epidemic. ...
snip... full text ;
JUNE 2006 VOL 2 NO 6 AGUZZI AND GLATZEL NATURE CLINICAL PRACTICE NEUROLOGY 329
www.nature.com/clinicalpractice/neuro
SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2004. SPORADIC CJD CASES TRIPLED, and that is
with a human TSE surveillance system that is terrible
flawed. in 1997 cases of the _reported_ cases of cjd
were at 54, to 163 _reported_ cases in 2004. see stats
here;
p.s. please note the 47 PENDING CASES to Sept. 2005
p.s. please note the 2005 Prion D. total 120(8)
8=includes 51 type pending, 1 TYPE UNKNOWN ???
p.s. please note sporadic CJD 2002(1) 1=3 TYPE UNKNOWN???
p.s. please note 2004 prion disease (6) 6=7 TYPE
UNKNOWN???
http://www.cjdsurveillance.com/resources-casereport.html
CWD TO HUMANS = sCJD ???
AS implied in the Inset 25 we must not _ASSUME_ that
transmission of BSE to other species will invariably
present pathology typical of a scrapie-like disease.
snip...
http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf
ATYPICAL TSEs in USA CATTLE AND SHEEP ?
http://www.bseinquiry.gov.uk/files/sc/seac17/tab03.pdf
TSS
