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OCR for page 108
Testing B/ood for Evidence of the
_ Agents of Transmissible
Spongiform Encepha/opathies
ellular degeneration of the central nervous system leads to the symp-
toms and demise of patients with transmissible spongiform encepha-
~ lopathies (TSEs). After the infectious agent of a TSE enters the host
though the alimentary tract or by a parenteral route, however, it travels
along extraneural pathways prior to neuroinvasion. During this extraneural
phase, prions invade the lymphoreticular system. Since lymphoreticular
cells, such as macrophages, follicular dendritic cells, and lymphocytes, can
circulate in the blood as well as in the lymphatic system, there is a theoreti-
cal risk of blood-borne transmission of TSE agents.
This theoretical risk has several implications and justifies an intense
search to develop laboratory tests that can detect prions in blood. One
implication is that a blood test might allow earlier diagnosis and treatment
for persons infected with a TSE agent. Another implication relates to ensur-
ing the safety of the blood supply. And a third implication is that individu-
als now deferred from donating blood could possibly be returned to the
donor pool. In the absence of such blood tests, an ultraconservative TSE-
related policy for the deferral (prohibition) from blood donation will re-
main in effect, influenced by unfortunate past incidents involving the trans-
mission of human immunodeficiency virus (HIV) and hepatitis C virus in
blood products that led the U.S. Food and Drug Administration (FDA) to
require tighter, more effective safeguards for the collection, processing, and
testing of blood (Hoots et al., 20011.
At present, all persons who have traveled to countries reporting bovine
spongiform encephalopathy (BSE) for specified time periods are deferred
from donating blood. This policy reduces the available pool of donors by 3
108
OCR for page 109
TESTING BLOOD FOR EVIDENCE OF THE AGENTS OF TSEs
109
to 9 percent (Dodd, 20021. Studies in 2001 showed that actual donations of
blood units had decreased by approximately 1 percent as a result of the BSE
deferral guidelines (Dodd, 20021. This deferral has a greater impact on the
military than on the civilian blood supply (a comparison of the military and
civilian blood deferral policies appears in Table 9-2 in Chapter 91.
ANIMAL STUDIES TO ASSESS TSE INFECTIVITY OF BLOOD
Most research on the detection of prions in blood is based on experi-
mental studies in animals. Excellent reviews of these studies have been pub-
lished (Brown, 2001; Brown et al., 1999, 2001; Evatt, 19981. Several differ-
ent animal species and different TSE agents have been used in these studies.
Most experiments used fewer than 20 animals; nearly all donor animals
were experimentally infected with the TSE agent; and in most cases, differ-
ent blood components were inoculated into the recipient animal by the in-
tracerebral route, the most sensitive form of in viva assay. In 20 studies,
involving five different donor-animal species, at least one assay animal re-
ceiving blood from experimentally infected donor animals was infected
(Brown, 20011. In no case, however, did blood or blood components from
naturally infected donor animals transmit disease to recipient animals. In
four separate studies, blood elements of sheep, goats, and cows infected
with scrapie and BSE agent, respectively, failed to transmit the agent to
recipient mice by the intracerebral or intraperitoneal route (Brown, 20011.
Animal studies investigating the transmissibility of blood-borne human
TSE agents have demonstrated transmission most successfully when the
animals were innoculated intracerebrally. For instance, the agent associated
with Gerstmann-Straussler-Scheinker disease (GSS) from the blood of do-
nor mice was transmitted to recipient mice intravenously, intraperitoneally,
and intracerebrally. The agent was successfully transmitted from 11 of 14
donor mice to recipient mice (Brown et al., 1999; Kuroda et al., 19831. In
addition, blood (huffy coat) of 10 of 28 donor guinea pigs experimentally
infected with the agent of Creutzfel~t-Takob disease (COD) infected recipi-
ent guinea pigs by the intracerebral, subcutaneous, intramuscular, and
intraperatoneal routes (Manuelidis, 19781. And the BSE agent, an acknowI-
edged TSE agent that can infect humans, was shown to transmit infectivity
to 4 of 48 mouse recipients when pooled plasma, obtained from blood
collected by heart puncture of 55 TSE-affected donor mice, was injected
intracerebrally into these recipients (Taylor et a.l, 20001.
Despite evidence in these animal studies that blood can transmit prions
experimentally, the majority of exposed animals were not affected even by
intracerebral inoculation. Furthermore, studies in which inoculation was by
the intravenous route demonstrated zero to low levels of transmissibility
(see Table 5-1). These results demonstrate that prion titers in blood are low.
OCR for page 110
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OCR for page 111
TESTING BLOOD FOR EVIDENCE OF THE AGENTS OF TSEs
111
However, recent work by Hunter and colleagues (2002) demonstrated the
ability to pass both the scrapie agent and the BSE agent from asymptomatic
affected sheep to normal sheep via blood transfusion. That study expanded
upon the single transfusion case reported by Houston and colleagues (2000)
2 years previously. Hunter's team reported that 2 of 24 recipient sheep
transfused with blood from BSE-infected donor sheep and 4 of 21 recipient
sheep transfused with blood from scrapie-infected donor sheep succumbed
to the respective TSE agent. This number of transmissions could increase as
the animals are followed for longer time periods. Transmission was demon-
strated using either whole blood or huffy coat. This study has significant
implications for assessing whether variant Creutzfel~t-Takob disease (vCTD),
a human BSE-induced prion disease, can be transmitted by a blood transfu-
sion. The study findings also have been used to provide further justification
for the precautionary donor deferral policy currently in place. Though it is
true that published studies to date have failed to demonstrate blood-borne
transmission of the infectious agent of sporadic Creutzfel~t-Takob disease
(sCTD) to nonhuman primates by any route (Brown et al., 1994), concerns
remain about possible transmission of the infectious agent of sCTD and
especially vCJD from blood and its products.
Other related research is ongoing. In a study funded by the European
Union, scientists at the German Primate Center in Gottingen are perform-
ing transmission studies with rhesus monkeys to elucidate the pathogenesis
of TSE in lymphoid tissue (personal communication, A. Aguzzi, University
Hospital of Zurich, October 12, 2002~. Baxter International Inc., a
Deerfield, Illinois-based pharmaceutical company, is conducting transmis-
sion studies with monkeys in an effort to understand the potential for prion
infection from blood products (personal communication, A. Aguzzi, Uni-
versity Hospital of Zurich, October 12, 2002~. The Commissariat a I'Energie
Atomique in Paris, France, plans to build a large new facility to house 60
macaques for TSE-related studies, including the infectivity of different prion
strains, such as those that cause vCTD (Deslys, 2002~. Yet more studies are
needed to determine whether the blood of donors infected with an agent of
CTD-particularly vCTD- can infect nonhuman primates.
A number of studies have increased our understanding of the distribu-
tion of TSE infectivity in the blood of infected animals. For instance, an
investigation into the concentration of TSE infectivity in various blood com-
partments of a mouse model showed a 4-fold higher concentration in the
buffy coat than in the plasma. The plasma had a 10-fold higher concentra-
tion of infectivity than the Cohn fractions, and the red blood cells had no
infectivity (Brown et al., 19981. In a follow-on study, the investigators
showed that during the early preclinical incubation period, the infectivity
compartmentalized in the same manner as in sick animals, but that the
infectivity was at much lower levels and was present in only trace amounts
OCR for page 112
2
ADVANCING PRION SCIENCE
in the plasma and the plasma fractions (Brown et al., 19991. Brown and
colleagues (1999) also demonstrated that infection by i.v. inoculation re-
quired seven times as much plasma and five times as much huffy coat as
infection by the i.c. route.
RISK OF HUMAN-TO-HUMAN TRANSMISSION OF TSE AGENTS
BY TRANSFUSION AND TRANSPLANT
Concern that human-to-human transmission of prions could occur
through blood products has been based, in part, on the knowledge that
human TSEs have been documented to result from the administration of
other human tissues or by contaminated instrumentation. A recent article
summarizes the 267 known cases of iatrogenic transmission of CTD (Brown
et al., 20001. They include transmission by corneal transplantation (3 cases);
stereotactic electroencephalography (EEG) (2 cases); neurosurgery (5 cases);
aura mater grafts (114 cases); pituitary-derived hormones (139 cases); and
gonadotropin (4 cases) (Brown et al., 20001. To date, not a single case
report of human CTD resulting from transmission by blood or blood prod-
ucts has been validated.) However, single case reports are difficult to prove
or disprove. Some case reports have suggested a possible association of CTD
with transfusions but those reports remain questionable (Collins and Mas-
ters, 1996; Klein and Dumble, 1993; Ricketts et al., 1997), necessitating
more appropriate epidemiological studies.
Many epidemiological studies have been conducted to assess the risk of
transmitting CTD among humans through blood products (see Table 5-21.
The least complex is epidemiologic surveillance. Surveillance systems have
not shown a concordant increase in CTD cases, as one would expect during
the past several decades, despite the increased frequency of using blood and
blood products (Evatt, 19981. A more complex approach, a case-control
study, is designed to determine whether exposure to blood is higher in CTD
patients than in a comparable group that does not have CTD. Several case-
contro! studies have failed to show such a difference (Davanipour et al.,
1985; Harries-Jones et al., 1988; Kondo and Kuroiwa, 1982; van Duijn et
al., 1998; Will, 19911.
iOn December 17, 2003, the United Kingdom's Secretary of State for Health announced a
case of vCJD in a 69-year-old man who had received a transfusion of packed red blood cells in
1996 from an individual who later developed vCJD (Department of Health [UK], 2003). This
single case does not prove that the blood transfusion transmitted the vCJD agent from the
donor to the recipient, but it does suggest such causality. The probability that the 69-year-old
developed vCJD independent of the blood transfusion is between 1:20,000 and 1:40,000 (per-
sonal communication, R. Will, The UK Creutzieldt-Jakob Disease Surveillance Unit, Decem-
ber 17, 2003).
OCR for page 113
TESTING BLOOD FOR EVIDENCE OF THE AGENTS OF TSEs
TABLE 5-2 Risk of Transmitting Human TSE Agents Through Blood,
Transplanted Tissues, or Surgical Instruments
113
T. .
ransmlsslon
Demonstrated?
Type of Study
Study Question
Yes No
Clinical case reports Can the infectious agent of a
TSE be transmitted from infected
human tissues by injection or
transplantation?
aura mater transplants X
corneal transplants X
human pituitary hormone
gonadotropin
reuse of surgical instruments
contaminated by prions
blood productsa
Epidemiological studies
X
X
X
surveillances Is there an increase in the number
of CJD cases commensurate with
the increased use of blood
transfusions ? X
case-controlc Are people who contract CJD
more likely to have received blood
products than people who do not
have CJD ? X
look-back Has the blood of donors with CJD
caused recipients of that blood to
develop CJD? X
high-risk groups (e.g., Do subpopulations that receive
hemophiliacs)e multiple transfusions exhibit a
higher-than-average rate of CJD? X
aRicketts et al. (1997).
bBelay and Schonberger (2002).
CEsmonde et al. (1993, 1994); Davanipour et al. (1985); Will (1991); Harries-Jones et al.
(1988); Kondo and Kuroiwa (1982); van Duijn et al. (1998).
Here et al. (1994); Satcher (1997); Dodd (2002).
eEvatt et al. (1998); Epstein (2003).
OCR for page 114
4
ADVANCING PRION SCIENCE
Another study design involves evaluating cohorts of recipients of blood
known to have been donated by a person who subsequently developed CTD.
These retrospective, look-back studies compare the occurrence of CTD in
this recipient population against the norm for the population. Two such
studies one of 27 recipients of blood from CTD donors and the other of
178 such recipients failed to show any cases of CTD in the recipients thus
far (Dodd, 2002; Heye et al., 1994; Satcher, 1997~. Another look-back
study in the United Kingdom examined 114 patients diagnosed with vCTD,
17 of whom had donated blood in the past. The investigators were able to
trace the blood products from 8 of these donor-patients; these consisted of
48 blood products, 22 of which had been transfused. None of those recipi-
ents were on the CTD registry. Of these original 114 patients with vCTD, 8
had received blood transfusions in the past. Four of these patients were
traceable and had received 117 blood components from 111 different do-
nors; 105 of those donors being traced, and none were on the CTD registry
(Dodd, 2002~.
Yet another approach is to study special high-risk populations, such as
hemophiliacs (Evatt et al., 1998), who receive many more blood products
than does the general population to determine whether they show an in-
creased prevalence of CTD. The majority of the blood-clotting factors they
receive is collected from multiple donors and pooled prior to use. The expo-
sure of these populations, therefore, is perhaps the highest of all possible
study populations. The U.S. Centers for Disease Control and Prevention
(CDC) has followed more than 12,000 hemophiliacs, and no CTD cases
have emerged (Epstein, 2003~. Another study reviewed pathological brain
tissue among 24 decedent hemophiliac patients from 144 hemophiliac cen-
ters who had died between 1983 and 1997; in no case was CTD diagnosed
(Evatt et al., 1998~. These studies provide some assurances for the lack of
blood transmission of TSE agents, but the inherent deficiencies of epide-
miological approaches, the rarity of the conditions, the difficulty of cor-
rectly diagnosing true cases, and the long incubation period prior to case
expression make these assurances both tentative and infirm. This is particu-
larly true for assessing the risk of transmitting the vCTD agent through the
transfusion of blood or one of its derivatives since this is such a new TSE.
BLOOD TESTS FOR TSE AGENTS
Sensitivity and Specificity
Given the theoretical risks for transmissibility of prions in blood or
blood products, the perceived need for a reliable screening blood test is
apparent. Absent such a test to clear persons exposed to the agent associ-
ated with vCJD, donor deferral, based on geographic history, will remain in
OCR for page 115
TESTING BLOOD FOR EVIDENCE OF THE AGENTS OF TSEs
115
effect, thereby shrinking the available donor pool. The lack to date of an
approved test to detect prions in human blood has a great deal to do with
the technical challenges of developing a test with sufficient sensitivity to
detect a single infectious unit (IU). The titers of prions circulating in the
blood of patients with sC]D or vC]D are not known at present, nor is the
quanity of prions sufficient to constitute an infectious unit in human blood.
Also unknown is whether the titer of the sC]D or vC]D agent in blood
might change and even revert to zero during the incubation period. This
information is particularly relevant to the agent of vC]D because it is ac-
quired from outside the body and because it travels a circuitous route
through peripheral systems on its way to the CNS. The dynamic nature of
the vC]D agent increases the complexity of designing antemortem diagnos-
tics for the disease.
In addition, the size and number of prion aggregates in a sample affect
the detection and removal of PrPSc from blood, blood products, and blood
derivatives. For example, if a blood or plasma sample contained an IU that
was a single prion aggregate containing 105 PrPSc molecules, the IU would
be relatively easy to filter out but difficult to detect, due to the low prob-
ability that a random sample would contain the aggregate. By contrast, if a
blood or plasma sample contained 1,000 PrPSc aggregates, each comprised
of 100 molecules, the aggregates would be much harder to filter out but
theoretically easier to detect as a result of the higher probability that a
random sample would contain an aggregate assuming the detection too!
were sensitive enough to detect a 100-molecule aggregate.
Recently, information gained from compartmentalized infectivity stud-
ies in a mouse mode! and a complex series of mathematical calculations
helped an investigator determine that 100 IU of infectivity (in huffy coat)
was equivalent to 10 picograms/mL of PrPSc (Brown, 20011. Brown used
this figure as an estimate target level that a future successful diagnostic test
would need to achieve, although he gave caveats that might alter this esti-
mate. Other models and methods need to be applied to reach more precise
estimates.
Recommendation 5.1: Fund research (1 ) to determine the amount
of sporadic Creutzfel~t-lakob disease (sCID) prions and variant
Creutzfel~t-lakob disease (vCID) prions in human blood and (2) to
estimate the amount of PrPSc corresponding to one infectious unit
of sCID and vCID prions in human blood. [Priority 112
Until one IU is determined for sCJD and vCJD in human blood admin-
2The committee denotes each recommendation as priority level 1, 2, or 3 based on the
criteria and process described in the Introduction.
OCR for page 116
116
ADVANCING PRION SCIENCE
istered to other humans, animal assays will need to be at least sensitive
enough to detect one mouse IU, within a specified transgenic strain, given a
specified volume and dilution of human blood, administered by the intrac-
erebral route. This would improve the consistency and reliability of an as-
say test.
Once the technical problem of developing a sufficiently sensitive test
has been solved, the other technical challenge is to develop a test so specific
that it can correctly identify a negative subject with a negative test result.
Failure to achieve this high level of specificity will result in false-positive
tests. This problem is especially acute in the case of C}D, which is uniformly
fatal, is associated with a prolonged asymptomatic incubation period and
has no effective prophylaxis or treatment. The psychological and social dam-
age to persons told mistakenly that they have C}D would be staggering.
This concern regarding false-positive test results is based on the statisti-
cal fact that the predictive value (correctness) of a positive test decreases as
the prevalence of the disease decreases in the population. For a rare disease
such as C}D, which occurs in 1 in 1 million persons, this is a thorny di-
lemma (see Table 5-31. If one had an excellent screening test for C}D whose
sensitivity and specificity were both an exceptional 99.9 percent and used
that test to screen 1 million persons, the percent correctness of a positive
test would vary with disease prevalence. If the disease being screened oc-
curred in 1 of every 100 persons, a positive test would be correct 91 percent
of the time. If the disease were rare, on the other hand, affecting 1 of every
1 million persons, the positive test would be correct less than 1 percent of
the time. In this case, with 1 million persons being screened, the true posi-
tive case would be correctly identified, but 1,000 persons would be incor-
rectly identified as positive. Thus only 1 of 1001 (0.1 percent) would be
correctly identified as positive, and virtually all the positive test results
would be false-positives.
The practical solution would be to perform a second- or third-level
confirmatory test that would be highly specific. That is how a similar di-
lemma with HIV screening is being approached. The HIV screening test,
despite having a specificity of 99.8 percent, has a predictive value of only 8
percent for a correct positive test (Dodd and Stramer, 20001. Follow-on
confirmatory tests are then used to verify to the initial screening test. Unfor-
tunately, such confirmatory tests for C}D or other TSEs are not available at
present.
Reporting Results and Counseling Donors Who Test Positive for TSE
There are additional concerns related to proper counseling and report-
ing of TSE screening tests. Most of these concerns focus on management of
consent for use of the test and notification of the test result. It is standard
OCR for page 117
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OCR for page 118
118
ADVANCING PRION SCIENCE
practice to advise blood donors about the tests to be performed on their
blood and to indicate that they will be told about any significant results. In
addition, at least in the United States, donors are notified of any deferral;
that is, any prohibition of further donation. Effective application of these
policies implies effective knowledge of the significance of the test and its
results. It is is unclear, however, whether accurate information about the
prognostic significance of a given test result will be available when a test
first becomes available.
It is appropriate that donors be provided with information that is con-
sistent with the current norms for informed consent. This information in-
cludes, but is not limited to, the purpose of the test. It also includes what is
currently known about the test, including the quantitative and qualitative
significance of a positive (or reactive) test result and the prognostic signifi-
cance of such a result, even if such data are available only from animal
models (Dodd and Busch, 20021. In addition, it is important to advise do-
nors about the risks associated with such a result, including the likelihood
of psychological trauma and other potential effects, such as the impact of
the release of the results on health insurance eligibility. It is also important
to specify the use to be made of the information by the blood collection
organization (for example, the possible discarding of donated products and
deferral of the donor). Procedures used to notify and course! donors about
test results should also be provided. There should be some mechanism, as
well, to permit a donor to opt out of having the test performed (which
would imply that his or her blood would not be drawn) or perhaps to
decline to receive the results. However, this latter option may be somewhat
illusory, as current standards require that a donor be notified of a deferral.
In the United States, there are few exceptions to the rule that donors are
notified of their test results. It appears extremely unlikely that a specific or
surrogate test for BSE or vCTD would qualify as such an exception. The
donor would be advised about the test result and, to the extent possible, its
quantitative (i.e., chance that the result is a true positive) and qualitative
significance. Provision of counseling and appropriate medical information
would be inherent in the notification process. In the event of the use of a
surrogate test, it would also be important to provide applicable information
about the significance of an abnormal surrogate marker itself, irrespective
of its putative relationship to TSEs (as is the case for a markedly abnormal
ALT sliver enzyme] level, for example).
Unfortunately, given the characteristics of TSEs and the absence of any
organized prospective studies on populations at risk of developing a spon-
taneous or foodborne TSE, it is unlikely that there will be any meaningful
quantitative or clinical information about the prognostic significance of a
positive test result at initiation of testing. Thus, the procedures outlined
above would be very difficult to put into practice. It would be useful, al-
OCR for page 119
TESTING BLOOD FOR EVIDENCE OF THE AGENTS OF TSEs
119
though daunting, to involve positive donors and, preferably, recipients of
their prion blood donations, in long-term follow-up studies, perhaps even
to the extent of performing postmortem assessments. At a minimum, peri-
odic assessments of marker levels and neurological status should be per-
formed.
It is difficult to escape the conclusion that if a test for BSE/vCTD were
implemented to reduce the risk from current donations, then prior dona-
tions from a test-positive donor would also pose some risk (particularly if
not previously tested). Thus, some form of look-back would be indicated,
suggesting a need for recipient notification. Indeed, the FDA currently rec-
ommends "medically appropriate notification and counseling . . . at the
discretion of health care providers" for recipients of blood from a donor
who is judged to be at (theoretical) risk of transmitting a TSE (FDA, 2002:
231. In the absence of any clear knowledge about the outcome of such trans-
fusions, however, the case for recipient notification is arguable. Such deci-
sions may best be made on a case-by-case basis, although current ethical
standards, at least in the United States, would tend to favor notification
(Dodd, 2001; Howe, 2001; Steinberg, 20011.
Much of the discussion around this topic is reminiscent of the concerns
expressed at the onset of testing for antibodies to HIV. Those concerns and
the associated problems were largely overcome and have set the scene for
current practice. It must be remembered, however, that AIDS (and of course,
HIV infection) had clear and well-established risk factors; many if not most
of those who were found to have a positive test result were not completely
unprepared for the news. In contrast, those who received indeterminate
results were greatly troubled, as they generally had no risk factors. This
latter situation may be more akin to the implications of a BSE/vCTD test in
the United States, where there is essentially (as of this writing) no risk for
indigenously acquired disease.3 Thus, the prospect of being tested may not
deter very many donors at the outset. However, a significant number of
well-publicized positive or false-positive results could generate concern and
apprehension about donating. The situation may well differ considerably in
countries such as the United Kindom, where the vast majority of the popu-
lation may perceive some degree of risk behavior associated with vCTD.
Indeed, surveys have suggested that as much as 50 percent of the popula-
tion might decline to give blood if a test were to be implemented. This
situation will probably depend to a large extent on the future dynamic of
the vCJD epidemic.
3EDITORS' NOTE: After this report was completed, the first U.S. case of BSE was identi-
fied in Washington State and was announced to the public on December 23, 2003.
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Regulatory and Commercial Considerations
The technical development and counseling issues discussed above are
not the only challenges involved in introducing a new screening test for
CTD. There are also commercial marketplace considerations and regulatory
requirements that will have to be met. Regarding the marketplace, the health
care delivery system in the United States is highly dependent on the private
sector, both for the provision of care and for the development of new drugs,
vaccines, and medical devices. Generally, demand for a product is a key
factor driving investment in the development of new products. The larger
the projected sales and profit for a new product, the higher is the priority
for that investment. In the case of CTD this disease is very rare; the preva-
lence of vCTD is near zero; there is no evidence for blood product transmis-
sion of either vCTD or sCTD to humans; and there is no mandate to screen
blood for CJD by the governing regulatory agency. Thus, any commercial
enterprise having finite resources to develop new products would have to
weigh those facts as it plans and programs its investment strategy. Market
forces clearly will play a role.
If the commercial sector were to develop and market a candidate screen-
ing test for CTD, that test would first need to be the approved by the FDA-
a methodical and time-intensive process. The FDA uses a variety of path-
ways and governing legislative codes to evaluate and approve medical
products. Screening tests for blood donors are regulated by the FDA as a
biological similar to vaccines. At present, the only requirements for testing
donors of whole blood and blood components are shown in Box 5-1; no
testing is required for CJD.
The manufacturer assumes risk and responsibility for conducting ex-
haustive studies to demonstrate that the product is safe, reliable, and accu-
rate. Test performance must be demonstrated in human clinical trials. Those
clinical trials can begin only after an investigational new drug (IND) appli-
cation to the FDA has been submitted and approved. The application must
show preclinical data that demonstrate proof of principle, performance of
the test with reliable reference materials, analytic sensitivity, and the effects
of interfering substances (Epstein, 20031. To date, no manufacturer has
reached this point for a blood test to detect CTD. Any new biological prod-
uct, including a blood donor screening test, receives intense scrutiny by
FDA regulators. Each test characteristic (see Box 5-2) must be thoroughly
evaluated. If one compares this list of characteristics with the status of a
screening test for sCTD/vCTD in human blood, significant shortfalls are ap-
parent. There are technical problems involved in achieving the needed sen-
sitivity. The lack of clinical specificity is a concern, and there is no confir-
matory test to recheck positive results. Manufacturing processes and tools
for prion detection in human systems are not proven. Variability of test
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results could be a problem in detecting COD since prion distribution in blood
may be evanescent and uneven. Variability may also be affected by test
reagents that have not been standardized.
In summary, the quest for a screening blood test must overcome many
hurdles before such a test can reach the marketplace. Scientists must under-
stand the biology of prions well enough to design and produce a prototype
test that is sufficiently sensitive and specific. Multiple testing schemes need
to be developed so that the result of one test result can be confirmed by
other tests. At the same time stable, standard, and reliable testing reagents
must be developed. The biotechnology industry needs to be properly con-
figured to successfully mass-produce a novel test product. Test users need
to develop ethically sound counseling and notification policies, especially
for those with a positive test result. Developers need to demonstrate and
document the performance of the test adequately to achieve FDA approval.
And finally, a market must exist, or be created, for the product to attract a
commercial manufacturer. While formidable, these obstacles can be over-
come with great resolve.
REFERENCES
Belay ED, Schonberger LB. 2002. Variant Creutzieldt-Jakob disease and bovine spongiform
encephalopathy. Clinics in Laboratory Medicine 22(4):849-862, v-vi.
Brown P. 2001. Creutzieldt-Jakob disease: blood infectivity and screening tests. Seminars in
Hematology 38(4 Supplement 9):2-6.
Brown P. Cervenakova L, Diringer H.2001. Blood infectivity and the prospects for a diagnos-
tic screening test in Creutzieldt-Jakob disease. Journal of Laboratory and Clinical Medi-
cine 137(1):5-13.
Brown P. Cervenakova L, McShane EM, Barber P. Rubenstein R. Drohan WN. 1999. Further
studies of blood infectivity in an experimental model of transmissible spongiform en-
cephalopathy, with an explanation of why blood components do not transmit Creutzieldt-
Jakob disease in humans. Transfusion 39(11-12):1169-1178.
Brown P. Gibbs CJ Jr, Rodgers-Johnson P. Asher DM, Sulima MP, Bacote A, Goldfarb LG,
Gajdusek DC. 1994. Human spongiform encephalopathy: the National Institutes of
Health series of 300 cases of experimentally transmitted disease. Annals of Neurology
35(5):513-529.
Brown P. Preece M, Brandel JP, Sato T. McShane L, Zerr I, Fletcher A, Will RG, Pocchiari M,
Cashman NR, d'Aignaux JH, Cervenakova L, Fradkin J. Schonberger LB, Collins SJ.
2000. Iatrogenic Creutzieldt-Jakob disease at the millennium. Neurology 55(8):1075-
1081.
Brown P. Rohwer RG, Dunstan BC, MacAuley C, Gajdusek DC, Drohan WN. 1998. The
distribution of infectivity in blood components and plasma derivatives in experimental
models of transmissible spongiform encephalopathy. Transfusion 38(9):810-816.
Collins S. Masters CL. 1996. Iatrogenic and zoonotic Creutzieldt-Jakob disease: the Austra-
lian perspective. Medical Journal o f Australia 164(10) :598-602.
Davanipour Z. Alter M, Sobel E, Asher D, Gajdusek DC. 1985. Creutzieldt-Jakob disease:
possible medical risk factors. Neurology 35(10):1483-1486.
OCR for page 123
TESTING BLOOD FOR EVIDENCE OF THE AGENTS OF TSEs
123
Department of Health (UK).2003. House of Commons Statement by the Secretary of State for
Health: Development in vCJD. [Online]. Available: http://www.doh.gov.uk/cmo/
vcjdstatement.pdf [accessed December 26, 2003].
Deslys JP. 2002. PrPres Diagnostics, Building Research Capacity, International Collaboration.
Presentation to the IOM Committee on Transmissible Spongiform Encephalopathies:
Assessment of Relevant Science, Meeting II. Washington, DC.
Dodd RY. 2001. Comment: Dilemmas of dementia. Journal of Clinical Ethics 12(2):141-142.
Dodd RY. 2002. TSEs and Transfusion Safety. Presentation to the IOM Committee on Trans-
missible Spongiform Encephalopathies: Assessment of Relevant Science, Meeting I. Wash-
ington, DC.
Dodd RY, Busch MP. 2002. Animal models of bovine Spongiform encephalopathy and vCJD
infectivity in blood: two swallows do not a summer make. Transfusion 42(5):509-512.
Dodd RY, Stramer SL. 2000. Indeterminate results in blood donor testing: what you don't
know can hurt you. Transfusion Medicine Reviews 14(2):151-160.
Epstein JS. 2003. Regulatory Considerations in the Development of TSE Screening Tests for
Donors of Blood and Plasma. Presentation to the IOM Committee on Transmissible
Spongiform Encephalopathies: Assessment of Relevant Science, Meeting 5. Washington,
DC.
Esmonde TF, Will RG, Ironside J. Cousens S. 1994. Creutzieldt-Jakob disease: A case-control
study. Neurology 44(suppl 2):A193.
Esmonde TF, Will RG, Slattery JM, Knight R. Harries-Jones R. de Silva R. Matthews WB.
1993. Creutzieldt-Jakob disease and blood transfusion. Lancet 341(8839):205-207.
Evatt BL. 1998. Prions and haemophilia: assessment of risk. Haemophilia 4(4):628-633.
Evatt BL, Austin H. Barnhart E, Schonberger L, Sharer L, Jones R. DeArmond S. 1998. Sur-
veillance for Creutzieldt-Jakob disease among persons with hemophilia. Transfusion
38(9):817-820.
FDA (U.S. Food and Drug Administration). 2002. Guidance for Industry: Revised Preventive
Measures to Reduce the Possible Risk of Transmission of Cruetzfeldt-Jakob Disease (CJD)
and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products. Rockville,
MD: FDA.
Harries-Jones R. Knight R. Will RG, Cousens S. Smith PG, Matthews WB. 1988. Creutzieldt-
Jakob disease in England and Wales, 1980-1984: a case-control study of potential risk
factors. Journal of Neurology, Neurosurgery and Psychiatry 51(9):1113-1119.
Heye N. Hensen S. Muller N. 1994. Creutzieldt-Jakob disease and blood transfusion. Lancet
343(8892):298-299.
Hoots WK, Abrams C, Tankersley D. 2001. The Food and Drug Administration's perspective
on plasma safety. Transfusion Medicine Reviews 15(2 Supplement 1):20-26.
Houston F. Foster JD, Chong A, Hunter N. Bostock CJ. 2000. Transmission of BSE by blood
transfusion in sheep. Lancet 356(9234):999-1000.
Howe KG. 2001. Comment: limiting toxic information. Journal of Clinical Ethics 12(2):143-
149.
Hunter N. Foster J. Chong A, McCutcheon S. Parnham D, Eaton S. MacKenzie C, Houston F.
2002. Transmission of prion diseases by blood transfusion. Journal of General Virology
83(Pt 11):2897-2905.
Klein R. Dumble LJ. 1993. Transmission of Creutzieldt-Jakob disease by blood transfusion.
Lancet 341(8847):768.
Kondo K, Kuroiwa Y. 1982. A case control study of Creutzieldt-Jakob disease: association
with physicalinjuries.AnnalsofNeurologyll(4):377-381.
Kuroda Y. Gibbs CJ Jr, Amyx HL, Gajdusek DC. 1983. Creutzieldt-Jakob disease in mice:
persistent viremia and preferential replication of virus in low-density lymphocytes. Infec-
tion Immunity 41(1):154-161.
OCR for page 124
24
ADVANCING PRION SCIENCE
Manuelidis EE, Gorgacs EJ, Manuelidis L. 1978. Viremia in experimental Creutzieldt-Jakob
disease. Science 200(4345):1069-1071.
Ricketts MN, Cashman NR, Stratton EE, ElSaadany S. 1997. Is Creutzieldt-Jakob disease
transmitted in blood? Emerging Infectious Diseases 3(2):155-163.
Rohwer RG. 2000. Titer, Distribution and Transmissibility of Bloodborne TSE Infectivity.
Paper presented at Cambridge Healthtech Institute 6th Annual Meeting Blood Product
Safety: TSE, Perception Versus Reality. McLean, VA.
Satcher D. 1997. Creutzfeldt-Jakob Disease and the Blood Supply. Statement at the July 31,
1997 Hearing before the House Committee on Government Reform and Oversight, Sub-
committee on Human Resources.
Steinberg D. 2001. Informing a recipient of blood from a donor who developed Creutzieldt-
Jakob disease: the characteristics of information that warrant its disclosure. Journal of
Clinical Ethics 12(2):134-140.
Taylor DM, Fernie K, Reichl HE, Somerville RA.2000. Infectivity in the blood of mice with a
BSE-derived agent. Journal of Hospital Infection 46(1):78-79.
van Duijn CM, Delasnerie-Laupretre N. Masullo C, Zerr I, de Silva R. Wientj ens DP, Brandel
JP, Weber T. Bonavita V, Zeidler M, Alperovitch A, Poser S. Granieri E, Hoiman A, Will
RG. 1998. Case-control study of risk factors of Creutzieldt-Jakob disease in Europe dur-
ing 1993-95. European Union (KU) Collaborative Study Group of Creutzieldt-Jakob
disease (CJD). Lancet 351(9109):1081-1085.
Will RG. 1991. Epidemiological surveillance of Creutzieldt-Jakob disease in the United King-
dom. European Journal of Epidemiology 7(5):460-465.
Representative terms from entire chapter:
test result
