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_ ~ Surveillance for Transmissible ;_ Spongiform Encephalopathies in the United States Comprehensive surveillance for transmissible spongiform encephalo- pathies (TSEs) in people and animals in the United States is in the best interest of public health and the economy. A number of na- tional and state programs are conducting limited surveillance of both ani- mals and humans. This chapter reviews present TSE surveillance programs and recommends strategies to improve and expand them. A new human TSE, variant Creutzfel~t-Takob disease (vCTD), was iden- tified in the United Kingdom in 1996 (Will et al., 1996) (see Chapter 21. Evidence that eating beef products containing the infectious agent of bovine spongiform encephalopathy (BSE) causes vCTD in humans (Coulthart and Cashman, 2001) has led many countries, including the United States, to conduct surveillance for both vCTD and BSE and to try to prevent the entry or spread of BSE within their borders. To date, no case of BSEi and no endogenous cases of vCTD have been detected in the United States. Although this country appears to be at low risk for these two TSEs (HCRA and TUCCE, 2001), the evidence that the infectious agent of BSE crossed the species barrier into humans has generated considerable concern about a uniquely North American TSE of animals chronic wasting disease (CWD). This fatal illness of deer and elk (described in Chapter 2) appears to have spread from its original location in Colorado and Wyoming to 10 more states and two Canadian provinces since the mid-199Os. The U.S. Depart- ment of Agriculture (USDA) declared a state of emergency in 2001 after a iEDITORS' 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. 125

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126 ADVANCING PRION SCIENCE CWD-infected cervid was discovered east of the Mississippi for the first time (USDA Office of the Secretary, 20011. Now, virtually every state has or is creating a CWD surveillance program. For these reasons, the committee believes more surveillance and epide- miological research should be conducted to ensure the early detection of a new human TSE, should one emerge; to monitor scrapie, the likely cause of BSE; and to monitor the spread of CWD. The first two sections of this chapter describe the surveillance programs in place to detect human and animal TSEs in the United States; included are recommendations for re- search that would strengthen these programs. The final section presents the committee's recommendations for research into the epidemiology and natu- ral history of TSEs; discoveries in these largely uncharted waters would improve U.S. capabilities to conduct surveillance for TSEs. U.S.SURVEILLA~4CE FOR HU MARE TSEs U.S. surveillance of human TSEs relies almost exclusively on mortality data because there is no uniform system for reporting human cases of these diseases as they are diagnosed. Only 12 states have made Creutzfel~t-Takob disease (CTD) a notifiable disease. Nevertheless, mortality data for human TSEs are a reasonable surrogate for incidence data because these diseases are uniformly fatal and have a relatively short clinical phase about 4 to 17 months. The United States conducts nationwide surveillance for human TSEs and studies their epidemiology through two principal organizations: the Centers for Disease Control and Prevention (CDC) in Atlanta and the Na- tional Prion Disease Pathology Surveillance Center (NPDPSC) at Case West- ern Reserve University in Cleveland, Ohio. CDC funds NPDPSC. Three forms of human TSEs are known to occur in the United States. The most common of these occurs spontaneously as the result of an un- known cause. Sporadic Creutzfel~t-Takob disease (sCTD) and sporadic fatal insomnia (sFI) fall into this category. The second form is due to mutations in the gene that codes for a prion, the protein thought to be the infectious agent of TSEs (see Chapter 21. The more than 50 distinct subtypes of this genetic form of human TSE are called by one of three names: familial Creutzfel~t-Takob disease, fatal familial insomnia (FFI), and Gerstmann- Straussler-Scheinker disease. The third and least common form of human TSE in the United States is due to transmission of the infectious agent through transplanted tissue or tissue extracts from an individual with a TSE or from surgical instruments used on a TSE patient.2 This illness is called iatrogenic Creutzfel~t-Takob disease (iCTD). 2vCJD is also infectious, but no endogenous cases of the disease have appeared in the United States.

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SURVEILLANCE FOR TSEs IN THE UNITED STATES latrogenic/l nfectious Genetic '0 5% ~ ~ pi \ 127 Sporadic ~88% FIGURE 6-1 The relative occurrence of sporadic, genetic, and iatrogenic forms of human TSEs in the United States, 1997-2002. SOURCES: National Prion Disease Pathology Surveillance Center (NPDPSC) (2003~; personal communication, P. Gambetti, NPDPSC, May 2003. Table 2-1 in Chapter 2 provides some detail on each of these diseases, all of which are rare and fatal. Of the nearly 600 U.S. cases of human prion disease examined neuropathologically from 1997 through 2002, the spo- radic forms accounted for approximately 88 percent of cases (the vast ma- jority being C]D), three genetic forms accounted for approximately 12 per- cent, and iC]D accounted for less than 0.5 percent, as shown in Figure 6-1 (NPDPSC, 2003; personal communication, P. Gambetti, NPDPSC, May 2003~. Through an analysis of mortality data, CDC determined that the rate and characteristics of human TSE deaths identified in the United States between 1979 and 2000 were stable over time and were consistent with the internationally accepted mortality associated with the disease (Belay and Schonberger, 2002~. The average annual age-adjusted TSE death rate in the United States from 1979 to 2000 was 1.07 cases per 1 million population (Belay, 2003), close to the worldwide rough annual average of 1 case per 1 million population. This finding suggests that endogenous vC]D has not occurred in the United States. A comparison of the age distribution of the United Kingdom's vC]D cases with that of the United States' sC]D cases further suggests that endog- enous vC]D has not occurred in this country. The median age at death of vC]D patients in the United Kingdom is 28 years (Andrews, 2003~. By con- trast, the median age at death among sC]D patients in the United States

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28 30 25 20 - 15 ADVANCING PRION SCIENCE vCJD* (n = 87) .S. CJ D** (n = 1,358) 10 - 5- O- r I I I 1 1 1 1 1 1 1 r ~ \ \ \ 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 5-year age group *Data as of May 1, 2001. **Non-iatrogenic cases, 1995-1999. FIGURE 6-2 Percent distribution of vCTD cases in the United Kingdom and sCTD cases in the United States by age group at death, 1995-2001. Reprinted from Belay and Schonberger (2002) with permission from Elsevier. Copyright 2002 by Elsevier. between 1995 and 2001 was 68 years. Figure 6-2 illustrates the strikingly different age distributions of vC]D and sC]D cases (Belay and Schonberger, 20021. In fact, less than 0.2 percent of noniatrogenic C]D patients in the United States died before the age of 30 (Belay and Schonberger, 20021. Table 4-1 in Chapter 4 provides a more extensive comparison of vC]D and sC]D. The one known U.S. resident with probable vC]D, a 23-year-old British woman who had resided in Florida since 1992, was born and raised in the United Kingdom during the BSE outbreak and is believed to have contracted vC]D from the consumption of infected beef products in her native country (Belay et al., 2003; CD C, 20021. She was still alive as of January 2004 (personal communication, E. Belay, C D C,January 16, 20041. At least 144 cases of vC]D, including the Florida woman, had been identified globally as of April 2003. The vast majority of these cases occurred in the United King- dom, but a few were identified in continental Europe, Hong Kong, and Canada.3 3The single cases of vCJD in Hong Kong and Canada are not considered endogenous be- cause the infected individuals had lived in the United Kingdom for an extended period of time during the BSE epidemic before effective controls were in place. Therefore, it is believed that these people became infected with the BSE agent in the United Kingdom.

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SURVEILLANCE FOR TSEs IN THE UNITED STATES 129 At present, four scientists conduct surveillance and epidemiology for TSE fatalities at CDC's Division of Viral and Rickettsial Diseases at the National Center for Infectious Diseases. In fiscal year 2003, $3.5 million was budgeted for the TSE group (personal communication, E. Belay, April 20021. In addition to salaries and research, these funds are intended to cover the group's overhead at CDC, operation of NPDPSC, and support for state-based TSE surveillance programs. The CDC team reviews passively reported cases of human TSE and analyzes national mortality data to determine the trends in human TSE among the U.S. population (Belay et al., 20011. Suspected deaths from TSE are referred to NPDPSC, which makes arrangements for autopsies, collects clinical data, performs neuropathological and neurohistochemical exami- nations on samples of brain tissue, and analyzes PrP and PRNP from brain and other tissues (see Box 6-11. CDC also monitors populations with a known risk of accidental infec- tion by priors, such as recipients of human growth hormone (Belay, 20031. CDC's epidemiologists have examined mortality records4 for evidence of 4The investigators searched for death certificates that listed as causes of death (1) hemo- philia A (International Classification of Diseases [ICD]-9 code 286.0), (2) hemophilia B (ICD- 9 code 286.1), thalassemia (ICD-9 code 282.4), and sickle-cell disease (ICD-9 code 282.6) (Holman et al., 1996).

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130 ADVANCING PRION SCIENCE diseases associated with increased exposure to blood or blood products (Holman et al., 1996~. Although substantial research has shown that sC}D and other long-known forms of human TSE are not transmissible through blood transfusions (Dodd, 2002; Foster, 2000), it remains unknown whether vC}D is transmissible in this manner. A hallmark of vC}D at present is the youth of its victims; therefore, CDC investigates all suspected cases of human TSE among those younger than age 55. To date, no evidence of endogenous vC}D or of other new variants of C}D has been discovered. As alluded to above, concern arose that the infectious agent of CWD had crossed the species barrier into humans after six cases of neurodegen- erative disease were detected in the United States in the l990s among hunt- ers and relatives of hunters (Belay et al., 2001; CDC, 2003~. However, follow-up investigations by CDC and state and local health authorities found no causal link between any of the six cases and CWD. The first investigation concerned three people aged 28 to 30 who died of C}D between 1997 and 2000 and who regularly ate deer or elk meat (Belay et al., 2001~. CDC aimed to determine whether the patients might have contracted a TSE by eating venison infected with the agent of CWD. The investigators concluded that the association of the three C}D patients with venison consumption "was more likely coincidental than causal" (Be- lay et al., 2001:1677-1678). In August 2002, CDC launched a similar investigation involving three men who died of neurodegenerative illnesses between 1993 and 1999 and who jointly participated in wild game feasts in northern Wisconsin (CDC, 2003~. The investigation revealed that the meat eaten at the feasts did not come from CWD-endemic areas. In addition, only one of the men had died of a TSE, and it was a common form of sC}D with no link to CWD. Thus, the investigators concluded that this second set of three cases also provided no evidence of a causal link between CWD and human neurodegenerative disease. National Prion Disease Pathology Surveillance Center CDC founded NPDPSC in collaboration with the American Associa- tion of Neuropathologists in 1996 to establish a national neuropathology laboratory for the analysis of human prion diseases (Belay, 2003~. NPDPSC examines the brain tissue and other informative tissues from all available5 possible and probable cases of human TSE in the United States. These ex- 5Many cases of human TSE in the United States are not identified, reported, or autopsied. This issue is discussed later in the chapter.

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SURVEILLANCE FOR TSEs IN THE UNITED STATES 131 aminations, outlined in Box 6-1' provide data for monitoring and charac- terizing the occurrence of human TSEs. In addition, NPDPSC stores the tissue samples it collects for research purposes. From 1997 through May 2003' NPDPSC received 1,095 referrals, of which 60.4 percent were definite cases of prion disease. Table 6-1 shows the number of cases diagnosed by the center annually for each type of hu- man prion disease. According to NPDPSC, these figures underrepresent the total number of human TSE cases that have occurred in the United States by about 50 percent. This conclusion is based on the following analysis. NPDPSC diagnosed 304 U.S. cases of human prion disease among the 5116 referrals it received during 2001 and 2002 (NPDPSC, 2003; personal communication, P. Gambetti, NPDPSC, July 12, 2003~. However, since an estimated 1.07 cases of prion disease per million U.S. population occurred annually between 1979 and 2000 (Belay, 2003), one would expect that about 597 cases oc- curred in the United States in 2001 and 2002, as shown in Table 6-2. There- fore, only 51 percent of the estimated number of actual U.S. human TSE cases were identified and referred to NPDPSC during 2001 and 2002. Several factors probably account for the low referral rate to NPDPSC. Some physicians may not recognize human TSEs as such. Some physicians or staff may inadequately document a suspected TSE death. Some individu- als who die of TSE may be misclassified as dying from other, more common neurodegenerative conditions. Finally, many diagnosed cases of human TSE are not autopsied. Increasing the U.S. Autopsy Rate for Human TSE Deaths The only way to diagnose a human TSE definitively is through a neuro- pathological examination. The estimated U.S. autopsy and referral rate of 51 percent for human TSEs prevents comprehensive surveillance for these diseases in this country. Unfortunately, the U.S. autopsy rate has been falling for more than 50 years (Hoyert, 2001). The general autopsy rate in the United States dropped from around 35 percent in the 1960s (Shojania et al., 2003) to 9.4 percent in 1994 (National Center for Health Statistics, 1996), the last year for which CDC tabulated autopsy data. By 2003, the national, nonforensic rate was estimated at 5 percent (Shojania et al., 2003~. In contrast, the 51 percent referral rate to NPDPSC is quite an achievement. Nevertheless, to improve U.S. surveillance for human TSEs, clinicians' 6The case of vCJD in 2002 is excluded.

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SURVEILLANCE FOR TSEs IN THE UNITED STATES 131 aminations, outlined in Box 6-1' provide data for monitoring and charac- terizing the occurrence of human TSEs. In addition, NPDPSC stores the tissue samples it collects for research purposes. From 1997 through May 2003' NPDPSC received 1,095 referrals, of which 60.4 percent were definite cases of prion disease. Table 6-1 shows the number of cases diagnosed by the center annually for each type of hu- man prion disease. According to NPDPSC, these figures underrepresent the total number of human TSE cases that have occurred in the United States by about 50 percent. This conclusion is based on the following analysis. NPDPSC diagnosed 304 U.S. cases of human prion disease among the 5116 referrals it received during 2001 and 2002 (NPDPSC, 2003; personal communication, P. Gambetti, NPDPSC, July 12, 2003~. However, since an estimated 1.07 cases of prion disease per million U.S. population occurred annually between 1979 and 2000 (Belay, 2003), one would expect that about 597 cases oc- curred in the United States in 2001 and 2002, as shown in Table 6-2. There- fore, only 51 percent of the estimated number of actual U.S. human TSE cases were identified and referred to NPDPSC during 2001 and 2002. Several factors probably account for the low referral rate to NPDPSC. Some physicians may not recognize human TSEs as such. Some physicians or staff may inadequately document a suspected TSE death. Some individu- als who die of TSE may be misclassified as dying from other, more common neurodegenerative conditions. Finally, many diagnosed cases of human TSE are not autopsied. Increasing the U.S. Autopsy Rate for Human TSE Deaths The only way to diagnose a human TSE definitively is through a neuro- pathological examination. The estimated U.S. autopsy and referral rate of 51 percent for human TSEs prevents comprehensive surveillance for these diseases in this country. Unfortunately, the U.S. autopsy rate has been falling for more than 50 years (Hoyert, 2001). The general autopsy rate in the United States dropped from around 35 percent in the 1960s (Shojania et al., 2003) to 9.4 percent in 1994 (National Center for Health Statistics, 1996), the last year for which CDC tabulated autopsy data. By 2003, the national, nonforensic rate was estimated at 5 percent (Shojania et al., 2003~. In contrast, the 51 percent referral rate to NPDPSC is quite an achievement. Nevertheless, to improve U.S. surveillance for human TSEs, clinicians' 6The case of vCJD in 2002 is excluded.

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134 ADVANCING PRION SCIENCE index of suspicion for this diagnosis must increase. Physicians and public health officials must identify more cases of human TSEs, more of those cases must be autopsied, and the relevant tissues must be sent to NPDPSC for a definitive diagnosis. Moreover, to identify new phenotypes of human TSEs, more cases of neurodegenerative diseases in general must be autopsied. Doing so would help CDC monitor the U.S. population for the theoretical transmission of CWD to humans. As noted above, there is to date no evidence that CWD is transmissible to humans. Should such transmission occur, however, the human form of CWD might bear little clinical resemblance to known hu- man TSEs hence the need to autopsy as many atypical cases of neurodegenerative disease as possible. The scientific history of FFI illus- trates this point. Unlike any other known TSE, the clinical hallmark of FFI is, as its name suggests, inherited progressive insomnia. Scientists began to suspect that FFI was a TSE only after neuropathological examination of FFI deaths revealed spongiform neurodegeneration (Manetto et al., 19921. Fur- ther studies confirmed the presence of proteinase K (PK)-resistant PrP in the decedents' brain tissues and a consistent point mutation (at codon 178) in their PRNP (Medori et al., 19921. The factors that contribute to the low autopsy rate of human TSE cases in the United States may include a cultural resistance to autopsies and the reluctance of most pathologists to conduct brain autopsies on suspected TSE cases for fear that the pathologist or his/her tools will become contami- nated. CDC is studying these issues through its Emerging Infections Pro- grams in New York and California (Belay, 20031. Preliminary data from a survey of pathologists in California indicate that about 80 percent of re- spondents do not perform autopsies on suspected CAD decedents because of concerns about infection control (Belay, 20031. In an effort to increase the referral and autopsy rates for suspected cases of human TSEs, NPDPSC began in December 2001 to cover the cost of an autopsy for a suspected CJD case; to identify institutions around the country willing to conduct reimbursed autopsies on suspected CAD cases; and, if necessary, to arrange and pay for the body to be moved to the closest location where an autopsy can be performed. If researchers found a way to inactivate prions on metal surfaces or remove prions from those surfaces, more pathologists probably would be willing to autopsy suspected TSE cases (see Chapter 71. In addition, the United States should evaluate and support ways to in- fluence neurologists, pathologists, and families to pursue autopsies of all cases of neurodegenerative disease, including suspected TSEs. One solution could be to communicate more frequently with pathologists and neurolo- gists to remind them of both the need to autopsy suspected TSE patients and the free services available for doing so. After the director of NPDPSC

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SURVEILLANCE FOR TSEs IN THE UNITED STATES 135 made a presentation about the TSE surveillance program at a national pa- thology meeting in 2000, the number of referrals to the center increased significantly. As of Tuly 2003, NPDPSC had approached five national asso- ciations of pathologists and neuropathologists in an effort to encourage their members to submit cases of suspected human TSEs to the center. Also, NPDPSC and CDC are seeking support from state health departments to urge American neurologists to report cases of suspected human TSEs (per- sonal communication, P. Gambetti, NPDPSC, April and July, 20031. Recommendation 6.1: Provide funds to promote an increase in the proportion of cases of human neurodegenerative disease, especially suspected cases of transmissible spongiform encephalopathy, that are recognized and autopsied. [Priority 217 The Need for More Epidemiological Research to Improve TSE Surveillance The committee sees a number of opportunities for the United States to improve its ability to detect a new human TSE, including a theoretical case caused by the infectious agent of CWD. Although CDC and NPDPSC have conducted many valuable laboratory and epidemiological investigations and analyses, the comparison in Table 6-3 of the United States' CJD surveil- lance program with those of the United Kingdom and Canada illustrates the relatively limited amount of resources that this country devotes to CTD surveillance and epidemiology. The improvement of U.S. surveillance for human TSEs will depend largely on information gleaned from epidemiological studies that help de- fine the target population and hone survey instruments. The 3 to 4 percent of autopsied cases that fall outside the classified subtypes of human TSEs could be studied further to determine whether a new human TSE lies among these atypical cases (personal communication, P. Gambetti, NPDPSC, March 26, 20031. Risk factors for CTD could be identified by studies that examined differences between CTD cases and controls. Comparing the age and geographic distribution of all neurodegenerative diseases in the United States with the distribution of all CTD cases might suggest regions in which CTD is underreported. In addition, the validity of death certification for CJD could be examined by comparing data on death certificates with re- sults of neuropathological exams. Death certificates also could be examined to determine whether significant differences exist between the demograph- 7The committee denotes each recommendation as priority level 1, 2, or 3 based on the criteria and process described in the Introduction.

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SURVEILLANCE FOR TSEs IN THE UNITED STATES 149 working group aims to foster the development of techniques for enabling each state to share the results of its unique CWD surveillance program such that the combined data could be analyzed on the national level (personal communication, Lynn Creekmore, USDA APHIS, October 10, 20031. In addition, the working group proposed a national program to certify herds of farmed cervids as being CWD-free (CWD Task Force, 20021. This pro- gram would require owners to report all cervid deaths and to have CWD testing performed on all animals (except calves) that are slaughtered or die on the premises. The committee supports the aims of the CWD Task Force's surveillance working group. We encourage the National Prion Research Program (NPRP) to fund projects that complement the group's activities. TSE Surveillance as an Antidote to Terrorism Adequate surveillance for TSEs is essential to discount and discredit terrorist hoaxes of planting BSE (WorId Health Organization, 20021. Re- search that helps produce better TSE diagnostics and better screening tests for infectivity would improve the United States' capability to conduct TSE

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150 ADVANCING PRION SCIENCE surveillance and provide convincing reassurance to the public, thereby un- dermining TSE agents as a tool for terrorism. The committee determined that TSE agents would be ineffective tools for terrorism if the objective were to create an epidemic of TSE. The diffi- culty of artificially infecting animals or people with the agents, the ineffi- cient transmission of the agents within and between species (except cervids), and the long incubation period of TSEs make TSE agents unlikely weapons. However, the lack of reliable diagnostic tests for TSEs and the limited un- derstanding of the epidemiology and pathogenesis of these diseases could provide the conditions for an effective terrorist hoax (National Research Council, 20021. For example, if either a BSE hoax or a real case of BSE were effectively planted, it could damage consumer confidence in beef products, resulting in significant losses to the beef and cattle industries. ESSENTIAL RESEARCH TO IMPROVE U.S. CAPABILITIES TO CONDUCT SURVEILLANCE FOR TSEs Many unanswered questions regarding the epidemiology, natural his- tory, and prevalence of animal and human TSEs in the United States ham- per the nation's ability to conduct the best possible surveillance for these diseases. The limitations of current diagnostic tools for TSEs also pose ob- stacles to comprehensive surveillance. The committee recommends that NPRP support the research outlined in Box 6-3 because the results of such research would not only improve the quality of TSE surveillance in the United States, but also would advance prion science in general. These re- search recommendations are discussed in detail in the following sections. Transmission Characteristics Although not a single case of C W D has been diagnosed in humans, BSE has crossed the human species barrier. Therefore, it is important to deter- mine whether the theoretical risk of C W D transmission to humans is real. Making this determination will require a substantial amount of experimen- tal and epidemiological research, although work along these lines has be- gun. For example, studies in a cell-free conversion model have shown that the infectious agent of C W D can convert human prion protein (Caughey, 2001~. New animal models, such as the ferret (Sigurdson et al., 2003) and mice with C W D transgenes, are being developed for use in C W D transmis- sion experiments, as are cynomologous macaques (Lasmezas et al., 2001~. Nonhuman primates are particularly valuable surrogates for assessing the risk of transmission of the C W D agent to humans. The utility of cynomologous macaques as human surrogates in TSE transmission studies was demonstrated through experiments that further established BSE as the

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SURVEILLANCE FOR TSEs IN THE UNITED STATES 151 cause of vC]D (Lasmezas, 20031. Lasmezas and colleagues showed that both the BSE and vC]D agents were readily transmitted to macaques by either the intracerebral (i.c.) or intravenous (i.v.) route, and that the trans- mission of either agent by either route resulted in the same histopathologi- cal lesions in the macaques' brains. Further, the scientists observed identical histopathological lesions in second-order macaques that were infected i.c. Or i.v. with either the vC]D or BSE agent from the previously infected macaques. These observations supported the hypothesis that the same prion strain causes both BSE and vC]D (Lasmezas et al., 20011. Moreover, Lasmezas and colleagues observed prions in the tonsils, spleens, and lymph nodes of the macaques observations also made in hu- mans with vC]D (Lasmezas, 2003 ). This finding suggests that cynomologous macaques would be excellent models for evaluating the risk

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152 ADVANCING PRION SCIENCE of iatrogenic transmission of vCTD to humans and the transmissibility of the CWD agent to humans by various routes. Studies are needed to determine the transmissibility of CWD not only to humans, but also to other animal species. Several investigations are un- der way to determine whether the CWD agent is transmissible to cattle. In one such study, 5 of 13 cattle inoculated i.c. with CWD-infected tissue from the same mule deer developed a disease resembling TSE (Hamir et al., 2001; Hamir and Miller, 2002; USDA and FDA, 20031. In another ongoing study, cattle exposed in 1997 to the CWD agent by either oral inoculation or contact with CWD-affected cervids had shown no evidence of transmission as of Tuly 2003 (personal communication, E. Williams, University of Wyo- ming, Tuly 11, 20031. Similar studies should be performed with other do- mestic and wild animals using various routes of transmission, including the oral route. For example, CWD transmission studies in cervids' feline preda- tors, such as cougars, would be valuable. Exposure Characteristics The natural routes and vehicles of exposure to TSE agents and the mechanisms by which the agents invade a host are well defined for some TSEs and poorly defined for others. Considerable epidemiological and ex- perimental evidence underscores the importance of the oral route, inges- tion, and alimentary uptake of the agents of scrapie in sheep, BSE in cattle, vCTD in humans, and transmissible mink encephalopathy in mink. Yet little is known about the routes and vehicles by which cervids are exposed to the CWD agent. Nor is it known whether the agent of CWD can infect pri- mates (as a proxy for humans) after oral or cutaneous exposure to CWD- infected cervid tissues. Investigations into the route or routes by which healthy cervids become exposed to CWD and into the mechanisms of CWD infection are under way at a few U.S. laboratories and field sites. The committee urges NPRP to support these long-term investigations and fund complementary ones. For instance, experiments should be performed to determine whether cynomologous macaques can become infected with the CWD agent through oral or cutaneous exposure. . . . . . . . Host Susceptibility Susceptibility to a TSE is believed to involve multiple host, agent, and environmental factors. Which factors play the most significant roles and how those factors interact are poorly understood. A principal host factor is the composition of the gene that codes for the PrP protein. Genetic variabil- ity along the PrP gene sequence in animals suggests that evolutionary pres-

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SURVEILLANCE FOR TSEs IN THE UNITED STATES 153 sure has led to the development of PrP sequences that are resistant to prion diseases. One of the best such examples is in sheep. Genetic resistance of sheep to the scrapie agent has been studied for decades. The polymorphisms at codons 136, 154, and 171 along sheep Prep have been recognized as major factors in determining resistance to scrapie. Three amino acids alanine (A), glutamine (QY, and arginine (R)- are encoded at those three sites. Sheep encoding ARR, especially those that are homozygous (ARR/ARR), are extremely resistant to scrapie. There has been only a single case of a sheep with an ARR/ARR genotype that devel- oped scrapie in nature. The sheep industry in the United Kingdom is taking active steps to inbreed ARR/ARR resistance into its flocks. Recently, how- ever, experimental i.c. inoculation of ARR/ARR sheep with the BSE agent led to the surprising observation that 3 of 19 sheep developed clinical symp- toms of TSE (Houston et al., 20031. This finding raises questions about the advisability of such inbreeding and suggests the need to investigate whether there is a difference in susceptibility to the scrapie and BSE agents in sheep. Much also needs to be learned about the genetic factors that determine susceptibility to human TSEs. We know that the PRNP gene in humans is polymorphic at certain locations; for instance, PrP may have either me- thionine or valine at codon 129. A recent report by Mead and colleagues (2003) suggests that human resistance to prion disease may be traced to early humans, whose practice of cannibalism placed them at risk of devel- oping fatal, kuru-like TSEs. The investigators hypothesized that this, in turn, resulted in selective survival of those resistant to TSEs. Individuals who are heterozygous at codon 129 of human PRNP appear to be more resistant to TSEs than those who are homozygous at that codon, according to this re- port, especially those who are homozygous for methionine. This hypothesis could explain the high frequency worldwide of heterozygosity at PRNP 129, the authors suggest, especially among the surviving female members of the Fore people who practiced ritual cannibalism (see Chapter 21. Distribution, Prevalence, and Host Range of TSEs The global distribution of TSEs is unknown because prion diseases could be occurring in areas where cases are unobserved or undiagnosed. Determining the extent of TSEs worIdwide will require not only better diagnostic tools, but also more extensive surveillance. Ecological research to improve sampling strategies, study animal movements and behavior, and develop nove! tracking methods would enhance the quality of TSE surveillance. It is likely that novel, undiscovered TSEs exist. They may be occurring in animals not previously known to have TSE, or known TSE agents may be presenting differently in new animal hosts. Surveillance systems must have

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154 ADVANCING PRION SCIENCE sufficient sensitivity to identify newly emergent TSEs or new presentations of TSE disease expression. The development of this capacity will require a multitude of surveillance methods and programs, and research to develop and sustain the necessary tools. Recommendation 6.4: Provide funds to expand research on the natural history, prevalence, distribution, exposure and transmis- sion characteristics, host susceptibility, and host range of transmis- sible Spongiform encephalopathies, especially chronic wasting dis- ease. [Priority 11 REFERENCES Andrews N. 2003. Incidence of Variant Creutzfeldt-Jakob Disease Onsets and DeatI7s in tI7e UK, January 1994-MarcI7 2003. Public Health Laboratory Service, Statistics Unit. [Online]. Available: http://www.cjd.ed.ac.uk/vcjdq.htm [accessed April 28, 2003]. Belay ED. 2003. CJD Surveillance in tI7e United States. Presentation to the IOM Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science, Meeting 4. Washington, DC. Belay ED, Schonberger LB. 2002. Variant Creutzieldt-Jakob disease and bovine Spongiform encephalopathy. Clinics in Laboratory Medicine 22(4):849-862, v-vi. Belay ED, Gambetti P. Schonberger LB, Parchi P. Lyon DR, Capellari S. McQuiston JH, Bra- dley K, Dowdle G. Crutcher JM, Nichols CR. 2001. Creutzieldt-Jakob disease in unusu- ally young patients who consumed venison. Archives of Neurology 58(10):1673-1678. Belay ED, Maddox RA, Gambetti P. Schonberger LB. 2003. Monitoring the occurrence of emerging forms of Creutzieldt-Jakob disease in the United States. Neurology 60(2):176- 181. Brown P. Cervenakova L, Diringer H. 2001. Blood infectivity and the prospects for a diagnos- tic screening test in Creutzieldt-Jakob disease. Journal of LaboratoryClinical Medicine 137(1):5-13. Cashman N. 2003. TI7e Canadian CJD Surveillance System. Presented to the IOM Committee on Transmissible Spongiform Encephalopathies: Assessment of Relevant Science, Meet- ing 4. Washington, DC. Caughey B. 2001. Prion protein interconversions. Pl7ilosopl7ical Transactions of tI7e Royal Society of London. Series B.: Biological Sciences 356(1406):197-200; Discussion 200- 202. CDC (Centers for Disease Control and Prevention). 2002. Probable Variant Creutzieldt-Jakob Disease in a U.S. Resident Florida, 2002. Morbidity and Mortality Weekly Report 51(41):927-929. CDC. 2003. Fatal degenerative neurologic illnesses in men who participated in wild game feasts Wisconsin, 2002. MMVDR (Morbidity and Mortality Weekly Report) 52(7):125- 127. Clark WW, Hourrigan JL, Hadlow WJ. 1995. Encephalopathy in cattle experimentally in- fected with the scrapie agent. American Journal of Veterinary Research 56(5):606-612. Coulthart MB, Cashman NR. 2001. Variant Creutzieldt-Jakob disease: a summary of current scientific knowledge in relation to public health. CMAJ 165(1):51-58. Creekmore LH. 2002. Clwonic Wasting Disease: Current Surveillance and Regulatory Re- searcI7 Needs. Presentation to the IOM Committee on Transmissible Spongiform En- cephalopathies: Assessment of Relevant Science, Meeting 3. Irvine, CA: Arnold and Mabel Beckman Center of the National Academies.

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