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From: TSS (wt-d6-175.wt.net)
Subject: Attributable testing for abnormal prion protein, database linkage, and blood-borne vCJD risks
Date: October 14, 2004 at 9:14 am PST

-------- Original Message --------
Subject: Attributable testing for abnormal prion protein, database [FULL TEXT]
Date: Thu, 14 Oct 2004 11:12:29 -0500
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@UNI-KARLSRUHE.DE


##################### Bovine Spongiform Encephalopathy #####################

Rapid Review
Lancet 2004; 364: 136264
MRC Biostatistics Unit,
Institute of Public Health,
University Forvie Site,
Cambridge CB2 2SR, UK
(S M Bird PhD)
sheila.bird@mrc-bsu.cam.ac.uk
Attributable testing for abnormal prion protein, database
linkage, and blood-borne vCJD risks
Sheila M Bird
Context National prospective collection of tonsillar tissue to be tested
anonymously for abnormal lymphoreticular
accumulation of prion protein (PrP) was approved to begin in the UK in
2004. The UK is not, however, testing autopsy
specimens attributably for abnormal PrP (PrPSC) so that recipients at
risk after a blood transfusion from, or exposed to
surgical instruments from, a deceased carrier of variant
Creutzfeldt-Jakob disease (vCJD) can be followed up to quantify
transmission risks. In Switzerland, surveillance for subclinical vCJD
includes unconsented testing in autopsies: consented
testing of tonsillar tissue is potentially attributable to interrupt
human-to-human vCJD transmission or treat it.
Starting point The UK announced its first case of probable blood-borne
vCJD transmission in December, 2003, and first
detected a case of probable blood-borne subclinical vCJD in July, 2004.
To reduce the possible risk of onward
transmission to other people, UK patients who had received
vCJD-implicated plasma products are being contacted.
They, and their general practitioner, are asked to inform anyone giving
them medical, surgical, or dental treatment, and
the patients must refrain from donating blood, tissues, or organs.
Where next? Prudent additional surveillance options for human
PrPSCparticularly at autopsy or to sanction the release
of quarantined operation sets pending effective decontaminationcan be
costed by reference to results for cattle and
sheep. Some ethical or legal impediments to the UKs
potentially-attributable testing for PrPSC may yet be rued.

Rapid Review
Scrapie is the endemic transmissible spongiform encephalopathy
(TSE) of sheep (and goats). Bovine spongiform
encephalopathy (BSE), a novel TSE in cattle, was
confirmed in the UK in November, 1986. Variant
Creutzfeldt-Jakob disease (vCJD), a novel TSE in human
beings,1 was first diagnosed in the UK in 1995, with ten
confirmed cases announced on March 20, 1996. vCJD, a
human form of BSE,2 is characterised by novel neuropathology
and younger age at onset, and only patients who
are methionine homozygotes at codon 129 of the prion
protein (PrP) have been clinically affected thus far. About
40% of the UK population has this genotype.
Lymphoreticular accumulation of PrP correlates with
the detection of protease-resistant PrP (PrPSC) by western
blot, is a consistent feature of vCJD at autopsy, and has
also been shown in the preclinical phase,3 which led to the
screening of large numbers of appendicectomy and tonsillectomy
samples.48 Hilton et al6 reported lymphoreticular
accumulation of PrP in three of 12 674
unattributably-tested appendicectomy and tonsillectomy
specimens from UK patients, 60% of whom were aged
2029 years at operation in 199599: a prevalence of 237
(95% CI 49692) per million in the retrospectively tested
age-group and time-period. Frosh et al,7 using
immunoblotting and immunochemistry, detected zero
positive cases out of 2000 anonymised tonsillectomy
specimens from 200002 (half from children under
9 years of age).
It is not known at what stage of vCJDs incubation
period PrP accumulation can be detected in lymphoid
tissue,4 but clearly the stage would affect test specificity
and vCJD projections. Uncertainty about the sensitivity of
screening will only be resolved by transmission studies or
following up positive testees to postmortem.
Blood-borne TSE risks
Blood-borne vCJD transmission8 was anticipated by other
countries bans on donors who had resided in the UK, and
by the UKs own precautions. Surveillance without consent
in recipients of at-vCJD-risk blood alerted the UKs
National CJD Surveillance Unit sooner than clinical
suspicion to the first case of probable blood-borne transmission,
and led to the first detection9 of transfusionrelated
carriage of PrPSC. It was prescient that relatives had
approved a postmortem in case one,8 and fortuitous that
autopsy was a medicolegal requirement in the second.9
Blood-borne vCJD transmission was harbingered by
scrapie and BSE transmission risks of 1020% in sheepvia
blood transfusion.10,11 The BSE-transmitting transfusion to
the first reported recipient-sheep which developed BSE
was made only half-way through the experimentallyinfected
donor-sheeps incubation period for BSE.10 Of
24 sheep-recipients of BSE-infected transfusions, two
were confirmed BSE cases (8%) and two others suspect
(transfusion risk up to 17 %). Of 21 sheep-recipients of
scrapie-infected transfusions, at least four had succumbed
(transfusion risk 21%).11
Blood-borne BSE transmission may, or may not, have a
role in the maternally-associated BSE-transmission risk,
first reported as 10% (95% CI 515%) to calves born in the
late incubation period of BSE-affected dams12 and then as
under 5%,13,14 but all analyses had to grapple with confounding.
In human beings, surveillance for death in
children of vCJD parents, an early recommendation,15 has
not been rigorously implemented because families were
reluctant to support the necessary record linkage.
How many at-vCJD-risk transfusion recipients have
survived for, say, 5 years after exposure (=R5) is unknown
5 years chosen for when PrPSC might be de-
Lancet 2004; 364: 136264
MRC Biostatistics Unit,
Institute of Public Health,
University Forvie Site,
Cambridge CB2 2SR, UK
(S M Bird PhD)
sheila.bird@mrc-bsu.cam.ac.uk
1362 www.thelancet.com Vol 364 October 9, 2004
Attributable testing for abnormal prion protein, database
linkage, and blood-borne vCJD risks
Sheila M Bird
Context National prospective collection of tonsillar tissue to be tested
anonymously for abnormal lymphoreticular
accumulation of prion protein (PrP) was approved to begin in the UK in
2004. The UK is not, however, testing autopsy
specimens attributably for abnormal PrP (PrPSC) so that recipients at
risk after a blood transfusion from, or exposed to
surgical instruments from, a deceased carrier of variant
Creutzfeldt-Jakob disease (vCJD) can be followed up to quantify
transmission risks. In Switzerland, surveillance for subclinical vCJD
includes unconsented testing in autopsies: consented
testing of tonsillar tissue is potentially attributable to interrupt
human-to-human vCJD transmission or treat it.
Starting point The UK announced its first case of probable blood-borne
vCJD transmission in December, 2003, and first
detected a case of probable blood-borne subclinical vCJD in July, 2004.
To reduce the possible risk of onward
transmission to other people, UK patients who had received
vCJD-implicated plasma products are being contacted.
They, and their general practitioner, are asked to inform anyone giving
them medical, surgical, or dental treatment, and
the patients must refrain from donating blood, tissues, or organs.
Where next? Prudent additional surveillance options for human
PrPSCparticularly at autopsy or to sanction the release
of quarantined operation sets pending effective decontaminationcan be
costed by reference to results for cattle and
sheep. Some ethical or legal impediments to the UKs
potentially-attributable testing for PrPSC may yet be rued.
For personal use. Only reproduce with permission from Elsevier Ltd
Rapid Review
tectable9,10 because the incubation period for transfusionrelated
vCJD is likely to be shorter than that for dietary
BSE exposure16 (no species barrier, intravenous route,17
and possibly higher exposure). That 1/R5 has developed
vCJD and another case, at autopsy, has tested positive
ranges from worrying to alarming. If 1000 diet-exposed
individuals16,18 are incubating blood-transmissible vCJD,
10% of whom donate four infectious units of blood, and a
quarter of their 400 recipients survive for 5 years postexposure,
R5 may be nearer 100 than the initiallyidenti
fied 15 (five of whom died without testing).8 Risk
heterogeneity19 might mean that only methionine homozygotes
manifest clinical disease. But, already, an elderly
heterozygous recipient9 who died from causes unrelated to
vCJD tested positive for PrPSC in the spleen. Only short
incubation times for human-to-human vCJD could be
observed thus far, so that risk may rise above 2/R5.
Active TSE surveillance in ruminants
Following Switzerlands lead,20 from January, 2001,
Europe-wide postmortem BSE testing of apparently
healthy cattle aged over 30 months and of fallen stock aged
over 24 months2124 has shown that clinical BSE cases
account for a third only of all BSE-test positives and that
BSE positivity is 1015 times higher in fallen stock. An
assumption of differential mortality in late-stage BSE led
to estimates that the UK had had nearer 4 million than
1 million BSE-infected cattle.23 TSE testing of sheep, with
genotyping, has confirmed higher TSE positivity also in
fallen sheep,21,22 and found apparent positives in sheep previously
considered scrapie-resistant (genotype ARR/ARR).
In human beings, retrospective, unlinked, anonymous
but un-genotyped testing of stored operative tissue5,6 has
revealed an unusual pattern6 of lymphoreticular accumulation
of PrP. Because all vCJD patients have been
methionine homozygotes, we do not know whether the
human PrPSC profile is altered by genotype, but the UKs
second transmission from a vCJD-incubating donor
indicates that it may be.9 As in bovines, there is at least a
three-fold discordance in prevalence between backcalculation
from vCJD cases18 versus the testing of
operative tissues.68
Active surveillance in human beings
Despite a higher TSE-test-positive rate in fallen stock and
presumed differential mortality in late-incubation, the UK
has instigated postmortem surveillance for PrPSC (with
genotyping) neither in human autopsies25 nor in deceased
persons exposed to at-vCJD-risk blood or surgical instruments.
In 2004, the UK excluded, as donors, recipients of
blood, plasma, or tissue; and, from Sept 20, 2004, has
asked recipients of vCJD-implicated plasma products to
inform in advance anyone treating them for medical,
surgical, or dental procedures.26 Preventing operative
transmission of vCJD and quantifying human-to-human
vCJD transmission risks need additional measures:
identification of index patients (incubating vCJD, positive
for PrPSC, or otherwise at riskeg, maternally or by percutaneous
exposure to BSE or vCJD blood) and their
recipients (of vCJD-implicated blood, plasma, tissue, or
surgical instruments), a recipients database of exposure,
risk-classification, and donor, with flagging of recipients
for mortality, and recipients agreement in life that they be
tested postmortem for PrPSC and genotyped.27
The table lists additional surveillance options. Surveillance
for death in patients whose tonsils are retained in
the national archive would mean that attributable tonsillar
testing can be done postmortem. Also, comparison of the
test result at tonsillectomy (if positive) and autopsy (if
done) would address the sensitivity of testing.
Attributable testing would also be done before blood or
tissue donation or elective surgery or during quarantine of
instruments (pending effective methods of decontamination28)
from emergency operation for any patient who
had undergone tonsillectomy in 2004 or later. The result
would be notified to patients according to their wishes,
national protocols,19 and future availability of treatments.
The table extends the national archives remit to
attributable testing for PrPSC of removed appendix (or
relevant other tissue) during quarantine of the instrument
set (to be destroyed for positive testees). Positive testees
would be flagged for mortality, alerted (or not) by their
wishes, and any previous network of recipients (blood,
tissue, or surgical) managed according to national guidelines.
19,29 Permission would be requested from alerted
index patients and their recipients for vCJD-informative
tests to be done in the event of their death; and safeguards
made to ensure these tests get done.
Although it is too late for primary prevention, attributable
tonsil (or other) biopsy for PrPSC at all autopsies in
patients aged 1554 years (with genotyping of positives)
facilitates identification, follow-up, and risk quantification
for recipients of at-PrPSC-risk blood or tissue or in a
surgical web from these deceased positive cases.
Costs in the rural context
The UKs international obligation is to quantify human-tohuman
vCJD risks. Spending of substantially more than
£1 million per prevented vCJD transmission will be
needed. Rural affairs give a context for costing human
surveillance and precautions. Germany tests 2∑6 million
www.thelancet.com Vol 364 October 9, 2004 1363
Option Explicit No opt-out
consent for: from:
Tonsil archive F+P T; FSC+RSC
Appendix removal PSC T; FSC+RSC
Autopsy aged 1554 ∑∑ A; RSC
Child of vCJD parent P F; RSC
Percutaneous exposure F+P RSC
to BSE or vCJD blood
F=flag for mortality. P=permission-in-life for postmortem PRPSC tests.
T=before blood or tissue donation, elective surgery, or
during quarantine of instruments, attributable test for PrPSC, alert
positives according to national protocol19 (eg, by CJD Incidents
Panel) and patient's wishes; archive test result. R=alert recipient
network, flag, and permission-in-life. A=at autopsy, test
attributably for PrPSC (eg, by tonsil biopsy or otherwise). Superscript
SC=do only for those attributably positive for PRPSC.
Table: Additional surveillance options in human beings
For personal use. Only reproduce with permission from Elsevier Ltd
Rapid Review
bovines a year and had around 50 confirmed BSEpositives
in 2003 at a cost of over £6 million per BSEpositive.
22 Ending the UKs Over Thirty Month Scheme23,24
for cattle born after July 31, 1996, would save about
£1 billion in 5 years but could incur one additional dietary
vCJD case.
Assume that the UKs affordable cost for finding an
unknown number of tonsil or operative positives to
prevent one vCJD transmission is between £1 million and
£1000 million. Suppose that among 200 000 testees,
positivity for PrPSC ranges from 4 to 40, 10% of whom
(without prevention-case-finding) would become blood or
tissue donors (ie, 0∑44 donors) giving rise to a mean of
four recipients each (1∑616 recipients), only a quarter of
whom are 5-year survivors (0∑44 longer-surviving
recipients), whose risk of human-to-human vCJD ranges
from 1/100 through8 r/15 to 20% (by ruminant analogy).
Resultant human-to-human vCJD cases could range from
0∑4/100 to 4/5. As a worse case, 500 000 tests on operative
tissue may give rise to 100 patients positive for PrPSC, and
at least one avoidable human-to-human vCJD
transmission.
Operation-positive-case-finding, if it meant screening
500000 tissues in 5 years, could not be done for only £2 a
test. But, even if screening were to cost £200 a tissue, the
cost of screening would amount to a tenth only of
preventing one cattle-to-human BSE transmission. On the
other hand, if blood-borne risks of vCJD transmission
were 100 times less, not even £1000 million would suffice
for their detection and management; and could be
described publicly as below an affordability threshold of
£1000 million over 5 years.
Finally, if testing cost £1∑5 million to discover one PrPSC
per 15 000 autopsies,8,22 its cost per detected PrPSC (and
recipient network) would still be only a quarter of
Germanys BSE-test cost per BSE-positive bovine.
Guardianship of public health is best served by timely
information about vCJD risks. Requirements for informed
consent in the UKs Human Tissue Bill could dangerously
delay autopsy surveillance for PrPSC.
I served on the UK steering group for studies of detectable PrPSC and the
European Union Scientific Steering Committees Adhoc BSE/TSE
Subgroup, and have received BSE-related funding from the MRC, Food
Standards Agency, and the Ministry for Agriculture, Food, and Fisheries.
References
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3 Hilton DA, Fathers E, Edwards P, Ironside JW, Zajicek J. Prion
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1364 www.thelancet.com Vol 364 October 9, 2004
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For personal use. Only reproduce with permission from Elsevier Ltdtss

www.thelancet.com

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