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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
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.
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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
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).
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).
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
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.
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
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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-
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.
20 ADVANCING PRION SCIENCE 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
TESTING BLOOD FOR EVIDENCE OF THE AGENTS OF TSEs 121
122 AD VANCING PRI ON SCIENCE 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.
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.
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.
