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II Guarding the Blood Supply

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The Retrovirus Epidemiology Donor Study: Rationale and Methods Thomas F. Muck I am going to briefly outline the rationale and methods of the Retrovirus Epidemiology Donor Study (REDS). I am going to provide no data except to look at the enormity of the database that has been accumulated. A request for proposals (REP) was published in 1988 by the National Heart, Lung and Blood Institute (NHLBI), because of the unknown infectious risk of transfusion, concern about HIV variants, the need to understand human T-lymphotropic virus (HTLV) infection, a need to create repositories to examine emerging infectious agents, and a need to evaluate emerging technologies to detect these agents. The study will run from 1989 to 1998, and it is likely that it will be extended beyond then. The purpose is to monitor the safety of the nation's blood supply through studies of the epidemiology of known agents, essentially retroviruses, among volunteer blood donors. What I am going to share with you today has recently been published in Transfus~on.37 Blood centers were selected on the basis of the quality of their proposals. There are four high-risk centers and one low-risk center, risk being defined as areas having a high background prevalence of AIDS. The REDS high-risk participants are the Red Cross Greater Chesapeake and Potomac, the Red Cross Southern Michigan, the Red Cross Southern California, and Irwin Memorial Blood Center. Oklahoma was considered to be low risk. The coordinating data center was Westat, Inc. The scope of the study is $40 million over the course of 5 years, and it is considered the most complicated study that NHLBI has ever launched. The structure is governed by a steering committee that has two investigators from each of the participating centers and the committee is chaired by an independent center director, who happens to be me. Subcommittees of this steering committee developed the proposals and protocols that we have been following over the course of the study. We have a continuing and an ongoing close relationship with the Centers for Disease Control and Prevention (CDC). 37Zuck, TF, RA Thompson, GB Schreiber, RO Gilcher, et al. (1995). The retrovirus epidemiology donor study (REDS): Rationale and methods. Transfusion, 35: 944-951. 27

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28 attitudinal issues. BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK There are five major REDS components: monitoring donors, creating a general repository, creating special repositories, studying a cohort of people infected with HTLV, and surveying donors concerning the prevalence of certain behavioral and Three substudies are pursuing these five objectives: establishing and maintaining a serum and cell repository, following the cohort of HTLV-infected donors and patients, and conducting the mail surveys directly. There are three REDS repositories: the General Serum Repository, the General Leukocyte and Plasma Repository (GLPR), and a Special Repository. Serum taken from donors routinely is selected at random based on a complicated sampling methodology devised by the statisticians at Westat. Samples in the special repositories are: donations that are repeatedly reactive for HTLV, but for which confirmatory testing is unclear; donations from sex partners of HTLV-positive subjects and their controls; donations that were repeatably reactive for HIV- 1 but which produced indeterminate Western blots; donations that were repeatedly reactive for HIV-2 but HIV-1 negative; and donations that were repeatably reactive for HIV but of unclear etiology. The HTLV cohort study uses a case-control methodology to investigate HTLV risk and transmission factors and to define the natural history of HTLV infection. Other than some studies in Kyushu, Japan, we know little about the natural history of HTLV infection. One of its outcomes, T-cell leukemia, is so infrequent that it is difficult to estimate how often it occurs once an infection has been identified. There were also few data on symptoms related to HTLV-associated myelopathy and tropical spastic paraparesis short of those two diseases themselves. They are actually identical conditions but defined in different parts of the world by different names. We were essentially searching for unexpected clinical outcomes, because in 1988, when this study was designed, the literature was unclear on the clinical outcomes of this infection.

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GUARDING THE BLOOD SUPPLY 29 The donor mail surveys were done in waves. The survey subjects were selected by sophisticated statistical techniques that randomized the selection of survey recipients. The resulting sample was enriched with donors from certain types of populations that we knew had high infection rates. The idea was to ascertain risk behaviors of the donors. The survey was stratified by several variables: center, race, age, sex, zip code, birth year, etc., trying to focus again on those people among the donor population who were more likely to engage in high-risk behaviors. This is randomized in a biased way in terms of enriching it for younger people. We mailed out about 64,000 questionnaires; the response rate was about 70 percent. The most important outcome is the extensive databases that are available for use today. We have demographic information Mom the donors of 4.9 million donations. The General Serum Repository contains 500,000 samples stored in multiple vials which are now the property of NHLBI. The GLPR has both leukocytes and plasma so that we can look at any kind of virus that may be only intracellular, such as HTLV, in which the genome is not free in the plasma. We have 546 HTLV-infected donors and patients who have been enrolled and who are being followed longitudinally for the presence or emergence of symptoms. The information in this database is immense and enormously valuable. To date, the surveys have found that more risky behavior is being encountered than predicted: up to 1 percent of people report prior drug use, sexual activity with a previous drug abuser, etc. The extensive data also permit incidence calculations. One of the difficulties we have had over the years is dealing with prevalence. We know what our current rate of infection in the donor base is, but in the past we could not look at incident infections, that is, in how many people per year does it occur? Those calculations are now being made. They contribute to the decision making regarding HIV antigen testing in a negative way. They show that antigen testing is probably not of great public health value. We have established an orderly process to access the database. An application is sent to the REDS Publication Committee, which looks at the request to see whether we want to provide a series of samples or process a request for data or data analysis. The committee then decides whether to recommend to NHLBI that the database or the samples be accessed for the requested purpose. NHLBI can veto the use of data or samples. This is particularly important for samples because once you have thawed them and then refrozen them, the test results gained from those thawed and refrozen samples have less credibility with certain kinds of testing technology. Thus NHLBI must carefully guard the repositories. The contributions of REDS to date have been important, and I have outlined just a few here that are by no means all inclusive. We were also involved with a team dealing with the idiopathic CD4 lymphocytopenia (JCL) crisis. Within days of the report of JCL, REDS formed a task force with CDC.

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30 BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK CDC had a meeting that included two Nobel laureates within 3 or 4 weeks of the announcement in Amsterdam. We used the laboratory facilities of REDS to work with the technology for CD4 counting. There were some recommendations from the panel convened at CDC that perhaps we ought to screen for CD4 counts. We quickly mobilized several REDS labs. We found that the technology was not available to do it practically with reliable results. It turned out that the data from people with JCL, so-called people with "AIDS without virus," were merely outliers in the normal variation of T-cells counted in blood donors, although it took us awhile to discover that. REDS was at the center of that, with incredible cooperation from the CDC. REDS also developed consensus conference data that were presented both at an NIH Consensus Development Conference and at the Blood Products Advisory Committee. These involved incidence data and window period estimates for viral diseases and how much we would close the window by antigen testing and whether there would be a magnet effect. REDS will continue to make general contributions to the risk literature. We are still probably the largest database of donors that can be accessed quickly with a great deal of accuracy. The Institute of Medicine report on HI V and the Blood Supply recommended continuing monitoring for risks in the blood supply. REDS is a very comprehensive database, and, importantly, can yield incidence data, and the use of incidence data is really the most reliable way to make decisions on what is happening. We can continue to track elements specified in the REP which are the data elements that I have outlined. Most importantly, as with ICE and the lessons with JCL, we were able to respond within days because we had the five centers in place. We had Westat crunching the numbers. We were able to respond in a way that no one else can because of the magnitude of the database that we have to deal with. One of the things that we might want to consider is not maintaining the current level of funding, but using a reduced level of funding to keep the REDS mechanism in place for the future so that we can respond and answer queries when we need to. It took us 18 months to set up this system. It was extremely difficult and it is extremely complicated, but it is in place now. It is on autopilot. It would be a pity if we lost the opportunity to have continuous surveillance and answer queries about unknown agents, new testing technologies, and the like.

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Demographic and Serologic Characteristics of Volunteer Blood Donors38 lames A. Koreli~z I would like to provide a brief overview of the demographic profile of blood donors in the Retrovirus Epidemiology Donor Study (REDS) as well as the prevalence of infectious markers that has been observed. I would then like to share with you the attempts to estimate the incidence of infectious disease markers, how incidence differs Tom prevalence, and how the incidence rate can be used in conjunction with estimates of periods of true positivity but seronegativity (window periods) to assess the risk of an infectious unit entering the blood supply. In addition to standard questions, such as those regarding gender and age, REDS collects information on additional donor demographics such as race, ethnicity, education, country of birth, and transfusion history. The standard battery of serologic tests is perfonned on all donations including tests for retroviruses and hepatitis viruses. A key feature of REDS worth emphasizing is that a unique donor identifier is created so that donations Tom the same donor can be linked for farther analyses such as the incidence analysis, as well as with other components of REDS. What are the demographic characteristics of blood donors? Based on approximately 2,000,000 donations (excluding autologous) collected during 1991 and 1992, we found that slightly more donations are from males than Tom females, more than 70 percent of donations are Dom the 20~9 age group, with about 10 percent from those under 20 and about 20 percent fiom those 50 and older, over 80 percent of donations come Dom white, non-hispanic donors, . and 38Talk presented at Forum on Blood Safety and Blood Availability, July 12-13, 1994. An updated analysis is given in Schreiber, GB, MP Busch, SH Kleinman, JJ Korelitz (1996). The risk of transfusion-transmitted viral infections. New England Journal of Medicine, 334: 1685-1690. 31

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32 BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK . donors are generally well-educated, 70 percent having some college experience and almost 90 percent being high school graduates. An important factor that will come up when we talk about incidence is the fact that 79 percent of our donations are from repeat donors and 21 percent are from first-time donors. It has been generally recognized that f~rst-time donors have a higher prevalence of infectious disease markers compared with repeat donors. With that demographic profile in mind, what kind of prevalence values are we observing? During 1991 and 1992, the prevalence of human immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV) were each about 1 per 10,000 donations. For hepatitis C virus (HCV), based on 19 months of data corresponding to when the supplemental HCV test was implemented at the blood centers, the prevalence was about 22 per 10,000. Prevalence gives us an idea of how many people are currently infected, or positive, for an infectious disease marker. It has obvious importance, especially from a broad public health perspective, for estimating the current magnitude of a health problem. However, prevalence does not provide us with any indication of when the infection occurred, and the timing of an infection is critical in the blood donor setting. After all, people who were infected long ago will show up as prevalent cases, but their donations will test positive and be excluded from the blood supply. A more important question relates to the rate at which negative donors are becoming positive, or seroconverting. People who have seroconverted will test positive, and their donations will be excluded, but people who are seroconverting may be in the window period where their donations are infectious but not detected by current tests. The definition of an incident case is fairly straightforward: it is when a donor who previously gave a negative donation shows up and gives a positive one. Remember that with REDS we have a linking donor identification number, so these donors can be identified. The incidence rate is then calculated as the number of incident cases divided by the total person-time observed. Let me give a brief example to explain person-time. Suppose person A gives two seronegative donations 18 months apart, and person B gives two seronegative donations 6 month apart. Neither one is an incident case, so we could say the incidence rate is O out of 2 donors. This method treats each donor equally. However, we would like to incorporate the fact that donor A was observed to remain seronegative for a longer time period than donor B. Likewise, suppose we observe two incident cases, or seroconverters, who initially give seronegative donations but subsequently give seropositive donations. The time between donor C's seronegative donation and seropositve

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GUARDING THE BLOOD SUPPLY 33 donation may have been 20 months, whereas the time between donations for donor D is 7 months. A way to express the incidence rate when subjects are observed for varying amounts of time is to say there were 2 cases per 51 observed person-months (18 + 6 + 20 + 7), or 0.039 cases per person-month. Thus, for each REDS donor, we determined whether or not they were an incident case, and the person-time between their first and last donations. Table 3 details each marker, the number of donors, the number of observed person-years, the number of incident cases, and the resulting incidence rate, expressed as number of cases per 100,000 person-years. The HCV rate is based on data obtained after the second generation screening test was implemented, so the sample size at this point is much smaller than for other markers. The hepatitis B virus (HBV) incidence rate is based solely on the HBV surface antigen (HBsAg) test. It does not include donors who went from negative to positive on the antibody to hepatitis B core antigen test. TABLE 3 Preliminary Results of Incidence Analysis39 Number of Number of Person- Incident Incidence Marker Donors Years Cases Ratea Anti-HIV 426,149 421,777 11 2.61 Anti-HTLV-I 426,134 421,767 3 0.71 Anti-HCV 151,708 62,444 4 6.41 HBsAg 426,101 421,734 28 6.64 Per 100,000 person-years. Although the rate for HTLV is based on only 3 incident cases, it is interesting that although the prevalence of HTLV was a little higher than the prevalence of HIV, the incidence of HIV is considerably higher than the incidence of HTLV. The next question is exactly how do you use, or what is the relevance of, an incidence rate? Using HIV as an example, exactly what does 2.61 cases per 100,000 person-years mean? The incidence rate, when it is a small number such as 2 or 3 per 100,000 person-years, is essentially equivalent to a probability, or risk. So we can say that if the rate is 2.61 per 100,000 person-years, the risk of a person seroconverting within a 1-year period is 1 in 38,000. Normally, we think of 39See Schreiber et al. (op cat) for an updated analysis.

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34 BLOOD AND BLOOD PRODUCTS: SAFER AND RISK using incidence rates or probabilities to predict the future. That is, we might say that 1 in 38,000 donors will become infected within the next year. But you could also use this figure to say that 1 in 38,000 donors were infected within the past year. The reason I make this distinction is that in the blood donor setting, the key question really is not "What is the probability that a donor will become infected after donating blood?" The critical question is, "What is the probability that a donor was infected before donating blood?" As I said before, if the donor was infected long enough ago, the serologic test will be positive and the donation will not enter the blood supply. For example, if everyone who was infected more than 6 months ago tests positive, then the question is, "What is the probability that a donor who shows up today to donate blood was infected within the past 6 months?" This is because only this infected donor will test negative and this donation might be used for transfusion. If we calculated a risk of being infected within the past year to be 1 in 38,000, then the risk of being infected within half of that time, or 6 months, should be half of the risk, or 1 in 76,000. Likewise, we can estimate the risk of being infected within any time frame to be proportional to the risk calculated on a "per year" basis. If we believe that the window period is 45 days, that is, only people who were infected within the past 45 days will have a negative serologic test today, then the risk of one of today's donors being such a person is 1 in 311,000. On the other hand, remember that we calculated our incidence rate from donors who gave at least 2 donations during our study period. What about first-time donors? It is generally assumed that first-time donors will have higher rates than repeat donors. To see what impact this can have, we can just assume a certain rate for first-time donors relative to that for repeat donors and weight that rate by the percentage of first-time donors in our study. For example, let us use the observed incidence rate of 2.61 per 100,000 person-years and say the window period is 45 days. If the rate in first-time donors is the same as that in repeat donors, then the risk is 1 in 31 1,000. But suppose the rate in f~rst-time donors is 50 percent greater than the incidence rate in repeat donors. This means that the rate in first-time donors is about 3.9 per 100,000 person-years. We observed, and other blood donor studies have also reported, that about 21 percent of donations come from first-time donors. So, if we count the 3.9 rate for 21 percent and the 2.6 rate for 79 percent, then the weighted average, when combined with a 45 day window period, adjusts the risk up to 1 in 281,000. Of course, the 50 percent increase was arbitrary. It could be 80 percent, 100 percent or some other value. One previous study estimated that first-time donors would have 1.8 times the incidence rate of

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GUARDING THE BLOOD SUPPLY 35 repeat donors.40 Table 4 delineates the impact of varying ratios of incidence rates for first-time versus repeat donors. The point here is that while the risk goes up, it is not overly sensitive to the unknown rate among first-time donors. TABLE 4 Adjusted Risk of HIV Transmission for First-Time Donors a If the ratio of incidence rates for first-time vs. repeat donors Is: Then the risk of window-period donation is: 1.0 1.5 1.8 2.0 1:3 1 1,000 1:28 1,000 1 :266,000 1 :257,000 a Assumptions are that donors have (1) an incidence rate of 2.61 per 100,000 person- years and (2) a window-period of 45 days, and that (3) 79 percent of donations from repeat donors. It is interesting to view this risk estimate in light of previous studies. Table 5 presents a partial list of risk estimates in the literature. This is a mixed bag of studies that used different study designs and methodologies to estimate risk. It does show a range of estimates, and depending on what range of variation you are used to working with, you might conclude that they are all in the same ballpark, or you might feel that the estimates are widely disparate. One important factor in looking at risk estimates for HIV is the time frame. As you know, we have had a very dynamic situation with HIV in teens of donor screening and testing. The studies are listed according to the year that the study ended. The risk estimate from each study is multiplied by 18,000,000, which is the number of donations or units that are collected each year in the United States, to get the number of window-period donations that would be expected to enter the blood supply each year. There appears to be a trend of decreasing risk with time; that is, more recent risk estimates appear to be lower than older risk estimates. This downward trend over time is what you would expect if you were decreasing the incidence rate (by effective donor screening) and/or decreasing the window period (by improved HIV tests). 40Cumming, PD, EL Wallace, JB Schorr, RY Dodd (1989). Exposure of patients to human immunodeficiency virus Trough the transfusion of blood components that test antibody-negative. New England Journal of Medicine, 321(14): 941-946. Comment in New England Journal of Medicine, 322(12): 850-851.

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56 BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK source of infection. Also, the system will be used to monitor the regional trends and variations in blood-borne infections. Finally, I would like to talk very briefly about the potential risk of Creutzfeldt-Jakob disease (CJD) being transmitted in blood products. Currently there is no evidence that it is transmitted in blood products. However, the risk cannot be assessed with any degree of accuracy. It is felt by everyone to be extremely low, if at all, and remains a theoretical risk at best. The troublesome thing is that it can be transferred to experimental animals by a transmittable agent, and the agent is present within the blood of the patients with CJD. That makes it a theoretical risk. The epidemiologic question is how do you do surveillance on a disease that has an incubation period of 20 to 30 years? It is not impossible, but it doesn't lead to any kind of ideal solution where you ascertain the risk very quickly. The hemophilia community is quite concerned about CJD, and they are anxious to have answers as soon as possible. The only way we can reasonably approach this problem is with a special study. Currently, 400 deaths occur annually in the hemophilia community in the United States. About 300 of these are caused by AIDS; the other 100 are caused by non-AIDS-related events. Of the 300 who die from AIDS, about 30 to 50 have central nervous system (CNS) AIDS. The hemophilia population has been routinely receiving concentrates for 20 and 25 years now. We would thus expect that if CJD was caused by a transmittable agent in blood products, you might be seeing cases now in individuals with hemophilia. The only condition that could be misdiagnosed would be individuals who have been diagnosed as having CNS AIDS. I have received several letters from individual physicians who treated hemophilia patients who had died with CNS AIDS before the publicity on CJD. There were no autopsies and no post- mortem examinations of these patients. Now these physicians are wondering if these might have been possible cases of CJD. It is this kind of rumor that spreads quite quickly in the hemophilia population because it is a very small, closed community. Both the physicians and the hemophilia patients now agree that the only solution to this is to try to obtain as many postmortem examinations as possible in individuals who die with CNS AIDS over the next several years. We have established a collaborative project between ourselves and Dr. De Arman at the University of California, San Francisco, the various hemophilia treatment centers, FDA, and NIH, as well as the various peer groups from the hemophilia population. We hope to obtain 10 to 15 brains per year for this study. The basic design of this study is to obtain permission at the time of death to remove the brain for a CNS autopsy. One-centimeter cubed biopsy specimens will be removed from the frontal, midparietal, and cerebellar regions and frozen. The remainder of brain will be placed in formalin for 2 weeks.

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G UP RDING THE BL OOD SUPPL Y 57 These specimens will then will receive a routine pathologic workup for dementia and an examination for the prion protein. Suspect cases will be reviewed by a panel of neuropathologists selected by ourselves, NIH, and FDA. A single case of CJD under the age of 40 would be very significant. A CJD case in an individual over the age of 40 could mean that we must continue this study, since a case of CJD in an older person won't carry the same weight as one in someone who is young. In summary, the collection systems, with the exception of CJD, which is a special study, are part of a national program designed to assist in lowering the complications of hemophilia. These data collection tools, however, can also be utilized very effectively to monitor blood-borne infections in this community and for observing whether there is any new incidence of unusual diseases. It may be that the only way that we will be able to obtain the information needed to monitor blood safety for relatively rare events or unknown events in a cost-effective manner. DISCUSSION Paul Russell: What evidence do you have that it takes 20 or 30 years for Creutzieldt-Jakob disease to be manifested? Bruce Evatt: It comes from several types of data. Some of it is Tom studies of cannibals in terms of kuru and other types of slow virus diseases. Certainly, the delay in onset was much shorter than 20 to 30 years in the cases of growth hormone-induced transmission. Thus, the delay is probably related to the dose of the agent, although it is probably related to other issues as well. David Rothman: When you made hemophilia a reportable disease, did you already know all about stigma? Do you have any built-in patient confidentially in any of these surveillance efforts? Bruce Evatt: Yes, we worried about a reaction from the hemophilia community. You have to understand that one of the issues that you deal with, confidentiality, is of utmost importance in this community, especially as it concerns HIV and AIDS. One of the problems we had during the 1980s was the fact that the hemophilia population didn't want to be identified. There was no registry of hemophilia patients. Even if you wanted to, you could not have notified them of risks associated with a new disease because they didn't want their names obtained by anybody. The lack of a registry in the hemophilia community has been a major issue. Obtaining a complete accounting of all individuals with hemophilia in the six states has been accomplished very successfully. We managed this in two ways.

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58 BLOOD AND BLOOD PRODUCTS: SAFER AND RISK First, the state health departments are the only entities that have the names. They have the right to do that in all of these states. They all have normal procedures to keep names confidential. In many states people in state health departments can go to jail for breaking confidentiality. Thus, they have a track record of maintaining confidentiality over a long period of time; that reassures people. Furthermore, there was an encryption of the identifiers. We do not know who, where, or what they are. It is to maintain a unique identifier for the database so that they can be followed subsequently by the state health department. The second way this was managed was that personnel Tom the state health departments met with the hemophilia chapters to explain the study. They told the chapters how the study is to the benefit of their community because it helps maintain resources and safety for them. Without this database in the system, they are at increased risk for unknown events. The personnel from the health departments regularly attended hemophilia board meetings, so that if there were complaints, somebody was there Mom the state level who could answer the questions and solved problems very quickly. One or two states ran into a few problems, but that was because of some unwise choices and not because they did not inform the community early and often. Those problems were also rectified, but it was not as smooth as in the states where they worked with the community in a more direct way. The hemophilia registries are unusual in that hemophilia is a chronic condition, whereas most diseases reported to state health departments are infectious diseases. However, in the states where this surveillance was implemented, the health departments are addressing the issues of chronic diseases. They are more sympathetic to these approaches than health departments in some of the states where acute diseases are the only things that are reportable. David Rothman: It is still a moderately scary precedent to have state legislatures pass these laws. James Allen: It is obviously a very complex problem. It is not only a chronic condition, it is also a genetic condition, and that has many other implications.

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CDC Surveillance for Unknown Pathogens Scott Wetterh all Surveillance has to be linked to public health action. The purpose of surveillance is to assess status, define priorities, evaluate programs, and stimulate research. The thesis that I am going to make, quite frankly, is that surveillance systems per se probably will not detect unknown pathogens or unknown etiologic agents. However, having ongoing surveillance systems provides a contact, an infrastructure, and a series of relationships such that detection can occur and a response can be mounted. Some fundamentals are needed to do surveillance, such as an organized health care system, a system for classifying disease and injury, and measurement techniques. Surveillance has many different activities. For the purposes of this group, I would focus on triggering investigations or detecting epidemics as the best uses for public health surveillance. You have heard about a number of different surveillance systems in the United States. Of these, the notifiable disease reporting system is the one that probably would serve as the basis for recognition of some sort of unknown pathogen or etiologic agent. This system exists in each of the 50 states and serves as a significant link between the Centers for Disease Control and Prevention (CDC) and the state health departments. There are other systems, and others are being developed-among them laboratory-based surveillance for antibiotic resistance patterns and hospital-based surveillance. What is a notifiable disease? Some people don't realize this, but CDC cannot designate which diseases are notifiable. This authority is within the purview of either the state health board or the legislature of any given state. When AIDS became a notifiable disease in the 1980s, it was because laws or regulations were passed in each of those states. CDC works with the Council of State and Territorial Epidemiologists to determine what the notifiable diseases are. We currently have 51 diseases on our list. Diseases are added and deleted from this list. For instance, Escherichia cold 0157 has been added, as has antibiotic-resistant Streptococcus pneumonias. Cases of these diseases are reported to CDC on a weekly basis. 59

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60 BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK You have heard a little bit about passive versus active surveillance. A passive system is one where physicians are required by regulation or law to report these diseases to local or state health departments. An active system, on the other hand, is one where reporting is initiated by a state health decal l~nent. The data are transmitted to CDC from state health departments electronically on a weekly basis and are published in the Morbidity and Mortality Weekly Report. For example, Figure 1 shows data tracking the decline in the number of cases or rate of malaria following World War II and subsequent rises primarily from returning veterans or foreign immigration. These data are available, and they are used to follow long-term trends. 1000 - ct too U) c' ~ to ce - Ct 0.1 a: l ~ Relaoses -- Overseas cases \ ~ Relapses from Korean veterans ~ Retuming Vietnam veterans /~\ JIBE / \/ ~ foreign immigradon ..... - . 0.01 1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 tam 1~ 1~5 FIGURE 1 Reported cases of malaria per 100,000 population in the United States, 19301992. How good are the data? Notifiable diseases carry with them regulations, fines, and various admonitions if a physician does not report a case of a particular notifiable disease. Yet we clearly know that there is a lot of underreporting. Table 7 presents data from Vermont comparing the number of patients hospitalized with notifiable diseases with the percentage of cases that are actually reported. Underreporting clearly is a problem, even though reporting is mandated by law.

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GUARDING THE BLOOD SUPPLY TABLE 7 Evaluation of Notifiable Disease Reporting, Vennont, 1982-198352 61 Disease Hospital Cases Percent Reported Hepatitis 64 31 Aseptic meningitis 127 6 Bacterial meningitis 65 62 Gonorrhea 30 95 Pertussis 15 40 Salmonellosis 63 67 We have similar data from Washington, DC. They are about 10 years older, but the trends have basically been the same. There is tremendous underreporting of disease, except when new diseases occur, such as AIDS. The case reporting for AIDS has actually been fairly good for two reasons: it is a relatively new disease and it is an exotic disease. Also, a lot of money was put into surveillance for it. There are several reasons for underreporting, and these are basically relevant to any surveillance system, particularly passive ones. There is often a lack of knowledge of reporting requirements, and there are negative attitudes toward reporting. There are misconceptions and even suspicion of the government and what it may be doing with this particular data. What are the ways to improve the surveillance system? Make it simple. Systems are often far too complex for what they are intended to do. Provide frequent feedback, widen the net, get increasing sources of information, and conceivably, do active surveillance. There has been talk about active surveillance. The advantages are that you can identify all the cases, you get better-quality data, and some of the data may be useful in special circumstances. The disadvantages are that it is incredibly time-consuming and costly, and the additional data may not be worth the cost, except in special circumstances. When new diseases emerge, we must have sufficiently simple, flexible, and acceptable systems already in place such that surveillance for these new pathogens or new disease entities can be incorporated into these systems quite readily. Using as an example the current attention being directed toward emerging infections, CDC is undertaking efforts to improve its surveillance activities in 52 Vogue, RL, SW Clark, S Kappel (1986). Evaluation ofthe state surveillance system using hospital discharge diagnosis, 1982-1983. American Journal of Epidemiology, 123: 197-198.

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62 BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK this arena. A number of major factors are contributing to the emergence of infectious diseases: human demographics and behavior, technology and industry, economic development and land use, international travel and commerce, microbial adaptation and change, and breakdown of public health measures. Increased population density and population encroachment, along with increases in international travel, are the same factors that would likely result in the introduction of some particular pathogen into the blood supply. The top seven emerging infectious diseases in 1993 were cryptosporidiosis, coccidioidomycosis, E. coliO157:H7 disease, multidrug-resistant pneumococcal disease, vancomycin-resistant enterococcal infections, influenza A/Beijing/ 32/92 virus infections, and hantavirus infections. I don't think these are necessarily ones that could be found in the blood supply, but the potential is always there for some emerging pathogen to find its way into the blood supply. These are new diseases or emerging diseases for which we need to fonn responses. Figure 2 provides data on the incidence of one of these, hantavirus. Hantavirus is a good example of the detection of a disease that wasn't previously notifiable. Emerging diseases are reported because people at the front line of public health (the public health nurses, physicians, primary care doctors, and medical examiners) notice an unusual syndrome and call up health officials. That is how you detect unusual or new diseases. 14 12 10 8 4 2 ~J S N |J ~ J S N 1992 1 1993 J ~J 1 994 FIGURE 2 Reported cases of hantavirus pulmonary syndrome in the United States, January 1-August 31, 1994 (1 1 cases prior to 1992 not shown).

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GUARDING THE BLOOD SUPPLY 63 There have been several notable instances of outbreak detection going back to the 1970s. Legionnaires' disease was first detected when a Veterans Administration pathologist came in to the morgue over the weekend and found three or four elderly men who had died from pneumonia. He called up a friend at CDC to report that something was going on. You know the story of AIDS in terms of a physician noting a cluster of illnesses in a certain group as well as the increased medication use that was alluded to earlier. Hantavirus was reported by a medical examiner who called up a medical examiner at CDC. E. cold 0157, which caused the famous multistate hamburger outbreak, was detected because a pediatric gastroenterol-ogist noticed hemolytic-uremic syndrome in a young child. The salmonella-contaminated ice cream outbreak that began in Minnesota was detected by the use of state lab serotyping data. In the state lab in Minnesota where the serotyping takes place, they found an increased incidence in one of the serotypes, which resulted in an investigation and detection of a multistate outbreak. Surveillance provides an infrastructure and relationships such that if something does happen, the person who notices something unusual can make the phone call. The calls can then be channeled to the appropriate persons. The CDC Epidemic Intelligence Service (EIS) is the active aim of CDC in terms of doing outbreak investigations. It was founded in 1951 because of concerns about biological and chemical warfare at the height of the Cold War and the Korean crisis. It is a training program that has graduated approximately 2,200 individuals from the program since its inception. EIS officers are not the only ones who may detect outbreaks, but the training program serves as a very useful informal network, linked by a yearly directory, for making contacts with our colleagues as we identify new and unusual things. We are ingrained Mom day one as EIS officers with the steps of an outbreak investigation: . . . . establish existence of outbreak, verify diagnosis, define and identify cases, and characterize by time, person and place. Then we must studies, and . develop hypotheses, evaluate hypotheses, refine hypotheses and conduct additional lab and environmental implement control measures.

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64 BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK You learn these in a relatively rote way, but you find that they are useful for almost any situation, including the unknowns. In the EIS network, 50 officers are currently have assignments in 26 state health departments. We have graduates in field epidemiology training programs in 19 countries. We also have a very active international visitor exchange program, such that often colleagues who are overseas detect things such as the Ebola virus outbreak in Zaire. They then give us a call and things begin to move along. It is an informal network, but it is a relatively effective one. It has worked well in the past in terms of identifying unknown pathogens. Finally, we are researching the history of the n otifiable disease surveillance system because it underscores a lot of interesting relationships between the federal government and states. Disease reporting is a state function, and Henry Baker, who was quite clairvoyant back in the beginning of this century, made this argument for collecting information on disease and health. "The only way to learn what diseases cause most sickness is to collect the statistics of sickness."53 That serves as our foundation for identifying new and unusual pathogens. We continue to do that. Hopefully, we can do a better job at it. DISCUSSION Bernard Horowitz: You described a system that was put in place several years ago that is an extension of an older one for monitoring hemophiliacs. One of the arguments is to assess blood safety. By the very nature of the treatment of hemophilia A or hemophilia B patients, who are largely treated with concentrates which are highly purified and virally inactivated with solvent/detergent or other other techniques, it is not as complete a reflection of safety from viruses as, for instance, the use of other patient groups such as those with thalassemia. Are you aware of comparable systems for other groups of patients, or in what way are you using rare hemophiliacs to understand the infectivity of donated blood? Bruce Evatt: I am not aware of other groups. I think that hemophilia patients are a unique group in that they are exposed to blood products from large numbers of donors. They are a sentinel group, but they now are also 53U.S. Public Health and Marine Hospital Service (1903). Transactions of the First Annual Conference of State and Territorial Health Officers with the United States Public Health and Marine Hospital Service. Public Health Bulletin, No. 11.

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GUARDING THE BLOOD SUPPLY 65 receiving more and more purified kinds of products. It is expected that their transfusion exposure will decrease in future years as they go to all recombinant products, except for the blood transfusions that they require. James Allen: If money is to be made available for surveillance for transfusion-transmitted diseases or special issues of that sort, we need to be certain that we have a very strong local, state, and federal disease investigation system and general surveillance process rather than looking to build a superspecialized type of vehicle for something unknown. Instead, our general surveillance system must be very strong. I have very real concerns about the strength of that today.

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