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From: TSS (
Subject: Transfusion transmission of vCJD: a crisis avoided? [LANCET FULL TEXT]
Date: August 6, 2004 at 9:02 am PST

-------- Original Message --------
Subject: Transfusion transmission of vCJD: a crisis avoided? [FULL TEXT]
Date: Fri, 06 Aug 2004 11:06:14 -0500
From: "Terry S. Singeltary Sr."
To: Bovine Spongiform Encephalopathy

Transfusion transmission of vCJD: a crisis avoided?

See Articles page 521
See Research Letters pages 527
and 529
See Comment page 479
In this issue of The Lancet, three reports examine issues about
the iatrogenic transmission of variant Creutzfeldt-Jakob disease
(vCJD). In a Research Letter, Alexander Peden and
colleagues report autopsy evidence of possible transfusion
transmission of vCJD in an individual who is a codon
129 methionine-valine heterozygote. Luisa Gregori and colleagues
report on the effectiveness of leucoreduction to
prevent transfusion transmission of prions. In the third paper,
Guillaume Fichet and colleagues identify a new technique for
disinfecting prion-contaminated medical devices. Together,
these reports provide further insights into the challenges of
managing the iatrogenic transmission of prion diseases. The
papers should also serve as an illustration of the benefits of
precautionary policy-making and as an example of the appropriate
integration of science into the policy process.

Precautionary responses to risk of vCJD
transfusion transmission

Concerns about the potential transfusion transmissibility of
vCJD emerged soon after the discovery of the disease in 1996.1
These concerns prompted three large UK recalls of blood
products that originated from individuals who later developed
vCJD.2 Precautionary measures were subsequently introduced
by several nations to protect against transfusion transmission
of vCJD, including the institution of leucoreduction and the
introduction of donor-deferral policies for individuals who had
travelled to regions endemic for bovine spongiform encephalopathy
(BSE).3,4 The UK has been the most aggressive in managing
the risk, instituting such policies as importing plasma to
manufacture fractionated products and deferring donations
from some individuals who have received a transfusion.5,6 At
the time these policies were introduced the risk of vCJD was
considered to be theoretical on the basis of existence of the
prion in reticuloendothelial tissue and the demonstration of
peripheral transmission via the oral route.7
Increasing evidence has emerged to suggest that vCJD is
indeed transfusion transmissible. The report by Peden and
colleagues further adds to this growing literature. In addition
to being only the second reported case of transfusionassociated
vCJD infection, the case reported is unique for two
main reasons: it presents autopsy evidence of infection,
presumably resulting from transfusion transmission from a
preclinical case; and it provides evidence of vCJD-related
infection in a codon-129 heterozygous individual. There are
some important caveats that must be considered when
interpreting these results. Primarily, the prion load was limited,
which could be a general feature of infection in codon-129
heterozygotes. Non-clinical infection has been previously
reported in animal models.8 As such, the true clinical and
public-health significance, with respect to the issue of whether
the individual would have subsequently developed clinically
evident vCJD or whether this individual poses a risk for
iatrogenic transmission of the disease, remains uncertain.
Nevertheless, combined with the animal studies by Houston
and Hunter and their colleagues9,10 showing transfusion transmission
of the disease in preclinical models, and the previous
case report11 of probable transfusion transmission, there now
appears to be sufficient evidence that individuals without
clinical signs of vCJD harbour, and therefore potentially transmit,
the infection (table). This accumulating evidence is a vindication
of the precautionary policies introduced by several
nations to manage what was, at the time, a theoretical
transfusion-transmission risk of vCJD.15 This approach to
policy-making represents an important shift from the
traditional evidence-based policy making model. Evidencebased
approaches would have required clear evidence provided
by well-designed epidemiological studies before the
institution of protective policies. The introduction of policies
to protect against a theoretical risk, which would reduce blood
availability and incur important costs, would have been viewed
as irrational. However, important lessons had been learned
from the application of such strict evidence-based models to
the risk of BSE and transfusion transmission of hepatitis C and
HIV. In both those instances, by the time the evidence arrived,
large numbers of individuals had been infected. Consequently
the precautionary principle, which essentially states that
complete evidence of risk does not have to exist before
measures are taken to protect against the risk, has been
advocated as an alternative model to strict evidence-based
policy making. By using this principle and by acting in advance
of complete certainty, policy makers have potentially protected
against vCJD emerging as a new large-scale blood-borne
However, it is important to recognise that the policy
response to vCJD was not successful for simply applying
precaution, but for the manner in which it was applied.
Precautionary-based decisions have had serious negative
outcomes; the refusal of some African nations to accept
genetically modified foods in the presence of famine and the
banning of DDT for malaria prophylaxis being two cases in
point.16,17 The fundamental difference between the response to
the threat of vCJD transfusion transmission and these
Transfusion transmission of vCJD: a crisis avoided? Vol 364 August 7, 2004 477
Level of evidence Evidence Year
Cohort studies None ··
Case-control studies None ··
Ecological evidence None ··
Case series None ··
Case reports Case report of vCJD infection identified in autopsy of
patient 2004
who received transfusion from donor with preclinical vCJD
Human case report of vCJD in recipient of transfusion from donor 200411
with preclinical vCJD
Animal evidence In primates, efficiency of BSE transmission via
transfusion shown 200412
to be at least as efficient as by oral route
Sheep-to-sheep transfusion transmission shown in animal models 20009
of preclinical and clinical disease 200210
Animal-model evidence of transfusion transmission of TSE 199813
Biological models Prion identified in lymphoid tissue 19977
Theoretical transfusion-transmission risk suspected on basis of 199614
demonstration of oral transmission of prion
TSE=transmissable spongiform encephalopathy.
Scientific evidence for possible transfusion transmission of vCJD
For personal use. Only reproduce with permission from Elsevier Ltd
precautionary responses was that the vCJD response was
proportional to the potential risk, and took into consideration
negative health-effects of the policy. Additionally, the policies
were constantly re-evaluated and modified as further evidence
of the risk of transfusion transmission of vCJD was obtained
and by the measured effect of the policies on blood availability.
Furthermore, whereas precautionary decision-making has
been previously accused of not appropriately using science, the
opposite has been the case with managing transmission risks
associated with vCJD.
Ongoing policy challenges
The fundamental challenge to policy making that emerges out
of the two case reports of vCJD transfusion transmission is the
significance of preclinical cases of vCJD and how to manage
their risk of iatrogenic transmission of vCJD. Without a test for
vCJD, measures need to be introduced to provide broad
protection to all potentially contaminated substances. The
second and third papers in todays Lancet provide some insight
into the scientific developments feeding policy responses to
this challenge. The experimental evidence that a large proportion
of prion infectivity might be attached to white cells
meant that leucoreduction was a potential strategy for reducing
transfusion risk from blood obtained from individuals
with preclinical disease. The strategy has been introduced on a
precautionary basis without clear evidence of benefit for
human transmissible spongiform encephalopathies (TSE).
Gregori and colleagues paper now suggests that the process
might only result in partial clearance of prions. Their study is
well designed and scientifically sound; however, it is not clear
that a hamster model is applicable to human beings,
particularly as the cellular distribution of prions varies widely
among species and strains of TSE agents. Assuming the results
could be translated to human blood products, an appropriate
use of precaution would, were there not other forces
operating, require re-evaluation of the evidence and potential
removal of the policy. However, leucoreduction confers other
benefits, including a reduction of non-haemolytic febrile
reactions, and has therefore also been introduced in countries
where the risk of vCJD is immeasurably low.18
Asymptomatic infected individuals could also pose a risk to
others if surgical equipment that is used on them is then used
on other individuals without appropriate decontamination. A
model for this form of transmission already exists with the
transmission of sporadic CJD via reused stereotactic electrodes
and neurosurgical equipment, and has required, from the
earliest assessments, the use of measures to mitigate the risk
of transmission through surgical procedures.19 In the UK, the
policy response has included upgrading disinfection facilities in
hospitals, the development of a CJD incidents panel, and
identification and tracking of surgical instrument sets.20,21 The
potential risk for such transmission of vCJD would presumably
be greater, given the higher prion load in these individuals and
the distribution of the prions through a wider range of organs,
including lymphatic tissue, than seen in sporadic CJD.22
However, the sterilisation of prions from equipment through
standard infection-control procedures has been a continuing
challenge because of the resistance of the prion to denaturing
and the damage that sufficiently rigorous measures have on
the equipment. The paper by Fichet and colleagues identifies a
new strategy to potentially decontaminate prion-infected
equipment without damaging delicate, expensive, and reusable
diagnostic and interventional equipment. If preclinical
cases are risks for iatrogenically transmitting the infection, in
areas where there is suspected to be a sufficient proportion of
these individuals an approach to protect surgical instruments
from contamination would have to be considered.
The potential risk of transfusion transmission of vCJD provides
a useful model for decision-making in the presence of scientific
uncertainty. The key lesson from this policy-making experience
is that lack of definitive evidence should not preclude action for
serious potential exposures. However, if precautionary action is
taken, the measures should be proportional to the risk and
consider the harms associated with the response. The policies
should be constantly re-evaluated as new science emerges on
the question, and policy makers and the scientific community
should work closely to ensure that the important gaps in
478 Vol 364 August 7, 2004
Prion protein
C and N are carboxy and amino terminals.
Science Photo Library
Rights were not granted
to include this image in
electronic media. Please
refer to the printed
For personal use. Only reproduce with permission from Elsevier Ltd
See Comment page 477
knowledge facing policy makers are being investigated. To
manage the ongoing threat of vCJD, policy makers will have to
continue to formulate policy in this manner. Other publichealth
domains addressing risk of a similar nature could also
learn from the vCJD experience.
*Kumanan Wilson, Maura N Ricketts
Toronto General Hospital, University Health Network, Toronto,
Ontario, Canada M5G 2C4 (KW); and Blood Safety Surveillance
and Health Care Acquired Infections Division, Population and
Public Health Branch, Health Canada, Ottawa, Ontario, Canada
KW is supported by a Canadian Institutes of Health Research New
Investigator Award. Neither KW nor MNR has any financial relationships
with other people or organisations that could inappropriately influence
work. At the time the vCJD-related policy decisions discussed in this
were introduced, MNR was working at WHO.
1 Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob
disease in the UK. Lancet 1996; 347: 92125.
2 Further precautionary measures on blood products announced.
Department of Health press release on CJD/BSE (United Kingdom 98/076).
Feb 26, 1998.
3 Government accepts advice on leucodepletion from Spongiform
Encephalopathy Advisory Committee. Department of Health press release
(United Kingdom 98/295). July 17, 1998.
4 Guidance for Industry. Revised preventive measures to reduce the possible
risk of transmission of Creutzfeldt-Jakob disease (CJD) and variant
Creutzfeldt-Jakob disease (vCJD) by blood and blood products. US
Department of Health and Human Services, Food and Drug
Administration, Center for Biologics Evaluation and Research (CBER),
Jan, 2002: (accessed July 28,
5 Boulton F. The impact of variant CJD on transfusion practices in the UK.
Transfus Apheresis Sci 2003; 28: 10716.
6 The vCJD Working Party of the Standing Advisory Committee on
Transfusion Transmitted Infections. Creutzfeldt-Jakob disease. Joint
UKBTS/NIBSC Position Statements, April, 2004: http:// www.transfusion
(accessed July 16, 2004). Vol 364 August 7, 2004 479
7 Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant
Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 1997; 349: 99100.
8 Hill AF, Joiner S, Linehan J, Desbruslais M, Lantos PL, Collinge J.
Species-barrier independent prion replication in apparently resistant
species. Proc Natl Acad Sci USA 2000; 97: 1024853.
9 Houston F, Foster JD, Chong A, Hunter N, Bostock CJ. Transmission of SE
by blood transfusion in sheep. Lancet 2000; 356: 9991000.
10 Hunter N, Foster J, Chong A, et al. Transmission of prion diseases by
transfusion. J Gen Virol 2002; 83: 2897905.
11 Llewelyn CA, Hewitt PE, Knight RSG, et al. Possible transmission of
variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004;
363: 42228.
12 Herzog C, Sales N, Etchegaray N et al. Tissue distribution of bovine
spongiform encephalopathy agent in primates after intravenous or oral
infection. Lancet 2004; 363: 4228.
13 Brown P, Rohwer RG, Dunstan BC, et al. The distribution of infectivity
in blood components and plasma derivatives in experimental models
of transmissible spongiform encephalopathy. Transfusion 1998; 38:
14 Flanagan P, Barbara JA. Prion disease and blood. Transfus Med 1996; 6:
15 Wilson K, Wilson M, Graham I, Hebert P. The application of the
precautionary principle to the health sector: lessons learned from decisions
concerning variant Creutzfeldt-Jakob disease and the blood supply.
Transfus Med Rev 2003; 17: 8994.
16 Roberts DR, Manguin S, Mouchet J. DDT house spraying and re-emerging
malaria. Lancet 2000; 356: 33032.
17 Masood E. A continent divided. Nature 2003; 426: 22426.
18 Hebert PC, Fergusson D, Blajchman MA, for the Leukoreduction Study
Investigators. Clinical outcomes following institution of the Canadian
universal leukoreduction program for red blood cell transfusions.
JAMA 2003; 289: 194149.
19 Brown P. Environmental causes of human spongiform encephalopathy.
In: Baker H, Ridley RM, eds. Methods in molecular medicine: prion diseases.
Totowa, NJ: Humana Press Inc, 1996; 13954.
20 Mayor S. UK government advises tighter measures to reduce risk of CJD
transmission during neurosurgery. BMJ 2003; 326: 51718.
21 Kirkup B. Incident arising in October 2002 from a patient with CJD in
Middlesbrough: report of incident review. DOH publication 28/02/2003: (accessed
July 16, 2004).
22 Frosh I, Joyce R, Johnson A. Iatrogenic vCJD from surgical instruments.
BMJ 2001; 322: 155859.

Mean times in transfusioncarrots and sticks for practice in

On July 22, 2004, a document entitled Emergency Planning
development of an integrated plan for the management of blood
shortages was issued by the UK Department of Health.1 This
report sets out a plan for managing any future shortages in
supply of blood to hospitals and outlines how blood will be
directed to where it is most clinically appropriate. A more
detailed action plan for hospitals is expected to follow soon.
This development has come as a result of deliberations within
a working group of the Chief Medical Officers National Blood
Transfusion Committee, which includes in its membership
representatives from hospitals, the National Blood Service, the
Department of Health, the medical Royal Colleges, and
specialist societies.
Why is this important? The supply chain for blood in the UK
starts with blood donated by voluntary donors (5·5% of the
population). In England the donations are processed by the
National Blood Service and issued to hospitals on demand. The
UK is self-sufficient in blood apart from fresh-frozen plasma
imported from USA for use in children born after 1996. These
children will not have been affected by variant Creutzfeldt-
Jakob disease (vCJD) from the food chain and the use of non-
UK fresh-frozen plasma will avoid potential exposure to vCJD
from UK donors. In April, 2004, concerns about human
transmission of vCJD by blood transfusion2 led to exclusion of
donors who have been previously transfused. The projected
loss of donors because of this exclusion is 3·2% of the current
base of donors (HIV-related attrition of donors peaked in 1982
at 6%). When a screening test for vCJD becomes available, it is
predicted that the donor base could fall further.
Because of the crisis related to transfusion-transmitted HIV
infection in the 1980s, transfusion services in high-income
countries introduced processes that improved the virological...


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