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Freireich, who at that time was a young investigator in the Cancer Institute (NCI), thought that sounded like a good idea. He went to his superior, a man by the name of (Dr.) Emil Frei–Frei and Freireich. Frei thought it was a good idea too, but he did not have much in the way of resources. So they put the idea to IBM who gave Judson a year’s leave of absence to come to NIH and work with Freireich in developing this instrument.
They had made such promising advances at the end of the year that the Cancer Institute then let a contract with IBM, which resulted in the eventual development of the first continuous flow blood cell separator. So, it was an interesting, sort of serendipitous way in which that was developed. What they thought they would be able to do was collect white cells and platelets. It turned out to be probably more important for collecting platelets, but it was also important back then for collecting white cells to treat infection in leukemia patients, as well as collecting platelets to treat patients’ bleeding problems when they were given chemotherapy.
A sidelight of that development is that the availability of that kind of instrument, not necessarily that particular instrument, has resulted in us being able to do gene therapy. In fact, what we do today is we separate out the cells and collect large numbers of lymphocytes with this kind of instrumentation and then we put genes into those cells as we grow them in the laboratory. Freireich’s foresight back in the 1960s is still being capitalized upon in 1993.
Harden: I will reiterate that we should come back again and talk about hepatitis and gene therapy. You seem to be in a key position for many different things in terms of what goes on at NIH.
Klein: Yes. I think that is because the Blood Bank has donors coming in and we have to prepare blood components that go to patients and we have a large bank of specimens that we can freeze away. Many things that happen in the hospital sort of traverse these corridors and laboratories, and have over the years.
Harden: In our discussion of AIDS, if my memory is correct, we had just gotten to 1984 and the discovery of the virus, or at least the publication of the papers that made everybody accept that there was a virus. You had talked about the Blood Bank’s–the Department of Transfusion Medicine’s–efforts to inform donors, and separate out, or if possible, self-select, donors. You were starting to tell us more about that when the interview came to an end, if you have recalled specific things that you wanted to say, please do so. I am interested, again, in how donor forms got modified and what else you did.
Klein: Yes. I wish we had more of these donor forms available, because there was a constant process of modification. It is hard to look back now and appreciate what was going on. First of all, as I think I said the last time, the Government takes a long time to print cards. They have to be printed in large numbers. All of the information that we had, and had given to donors, will not exist on the printed cards, most of which are on microfilm. What we did, in order to respond more rapidly, was something like this. As soon as it appeared that was an increased risk in some activity, or an additional piece of information became available, we updated two kinds of materials. One was a booklet that we have used, and still have outside, which contained relatively short informational material, that was given to donors. We started this, I think, about the middle or first quarter of 1983 and continuously updated it. It was simply a piece of educational material. The second item that we had was a sheet that was a pseudo-legal document. It was always no more than a single page, always had a place for the donor’s name, the date, and a witness’s name and date. The witness, who was the screening person, would ask questions and the donor would then sign that the questions had been asked. The witness would also sign. Then, somewhere on the donor card, there has always been a statement like, “I have been asked and have understood all of the issues involved in blood transfusion,” but it might not say, “I have been asked all the questions regarding AIDS.” That might not appear on our donor cards.
Harden: I am a donor and I recall a list of questions on the donor card which, as far as I know, never refers to “AIDS” per se, although some of the symptoms are fairly recognizable. But there are other questions that might lead the reader to think of hepatitis or malaria. “Have you traveled outside the country?” So the donor card speaks to a variety of diseases. Then there is the little yellow card that folds over. I asked particularly about why that was instituted.
Klein: Before we get to that one, let us get back to the regular donor card which now does say “AIDS” on it. But what it said is that, among the risk activities, is whether you are a gay male, or a man who has had sexual contact with another man since 1977. It also asks whether you have had contact with anyone who has had AIDS. The card lists the risk activities, and AIDS does appear and has since about 1985. I am not exactly sure when it was added to the card, as opposed to being added to, say, one of these throw-away pamphlets–it is not a throw-away; these were saved for a long period of time and then eventually discarded–but they were not part of the card.
The other card that you refer to is called the confidential unit exclusion, or CUE. We introduced those, I believe, toward the end of 1985. We introduced them in the belief that we might be getting individuals who are called in by us or who walk through the door. They sit down and we screen them, and sometime either during the course of screening, or after screening, it occurs to these individuals that, in fact, they are in a risk group but they just do not want to tell the screener. It is embarrassing for them, for whatever reason. So we, along with several other blood banks– the New York Blood Center, for example, was one of them–were relatively early in introducing confidential unit exclusion. The way we introduced it was to have a card that the donor would fill out that would say, “You can use my blood for transfusion, or you can use by blood only for research purposes.” That card did not have a name on it; it only contained a number. The donor was required to fold up the card and turn it in. The card would be opened up in the laboratory, and if it said “Use my blood only for research,” then that donor’s blood would never be used for transfusion. In fact, that donor would be removed from the list of individuals who would be donating for patient purposes.
As with so many things that sound easy and wonderful, we found, after we started to look at the process, that a number of people simply did not understand the reason for it. Some felt, “Today I would like my blood to go to research, and next week I would like it to go to a patient.” The actual method did not work perfectly. We changed the wording on the card several times in order to try to get the message across, and we still use a modified form like that, a confidential unit exclusion.
Harden: I presume you also find that as more and more people become sophisticated in understanding AIDS and about whether or not to exclude themselves, there are probably fewer instances where people realize half way through the form that they are in a risk group.
Klein: Yes. Some studies now suggest that this is no longer an effective way of screening out donors who are at risk. We will probably drop it as a way of proceeding simply because it does not seem to be effective any more. People are now much more aware of what the risks are.
There were several other ways of screening that we considered. One way was to give everyone a telephone number and say, “If you don’t want your blood to be used for transfusion, call this number any time of the day or night.” We actually did a study calling blood centers around the country and sending them a questionnaire to see what the efficacy of the various methods of confidential unit exclusion were. We published the results in Transfusion. The call-back system does not work. So, not only did we institute a CUE, but we tried to evaluate the national effectiveness of CUE, and people simply did not call back. If you looked at the blood that was excluded and the blood that was accepted, you could see that the markers were higher, first of all, in blood where people self-excluded. Those units had higher markers for hepatitis and, in some instances, for HIV. In places that used the telephone call back, their percentage of unit exclusions was much lower and, in general, their markers were higher in the units that were being used. This suggested against that people simply did not take the trouble to call back. Once a person was out of the facility, if he or she had not done everything while there, that was sort of the end of it.
Harden: All of these units of blood, were, no matter what the donors put on the exclusion card, I presume, tested for HIV as soon as a test was developed. What happens in terms of the donor, if the donor has thought that he or she was not infected and then you get a positive test?
Klein: Now this is frequently misunderstood. The actual procedure is the following. The blood is tested for the antibody for HIV by what is known as an ELISA test. If the blood goes through the test and the test come back reactive, then that unit is retested in duplicate. If either of those duplicates is reactive, then the test is positive. If both of those duplicates are not reactive, then the unit is still discarded, but nothing is done with the donor.
If the unit is positive, because one of the duplicate tests has been reactive, we then call it repeatedly reactive. The first screen was reactive and one or more of the duplicates was reactive. If it was repeatedly reactive, then in this center we would send the specimen for an additional test. Some people have called it a confirmatory test, but the FDA (Food and Drug Administration) does not like that term. It is an additional test, which is called a Western blot. If the unit of blood is Western blot positive, we consider that a true infection. We would call the donor, or notify the donor, by asking the donor to come in, that he or she was infected with the virus. Automatically the donor would be eliminated from ever donating blood, but the donor would also be counseled about what the test results meant.
In this institution we had a study for donors whose blood tests were positive for HIV and so the donor would be offered the opportunity to enter into a study for longitudinal follow-up.
Now, if the donor was repeatedly reactive with the ELISA test but this additional test, the Western blot, was negative, we would still, of course, not use the unit of blood. In the Blood Bank at NIH we also called in the donor. We would try to explain to the donor that he or she had a positive test but we were not sure that he or she was infected. It is very difficult to do. We had an enormous advantage because we could offer the donor the opportunity to be followed longitudinally with this as well. If the donor was at risk, was in fact infected, we would probably find that out. If the donor was not infected, we would probably find that out too. So at least the donor was under surveillance by what was, at the time, probably the most sophisticated laboratories in the country with regard to this issue and with the most knowledgeable physicians at the time in charge.
Other places faced a real dilemma. What should they do with a repeatedly reactive donor? Should they tell him or her that they were not sure that the donor was infected with the virus, but he or she should never show up again as a donor and that their blood could never be used again. A very difficult message. I think people tend to underestimate the impact that information has on an individual, on an individual’s family and on an individual’s practices, when he or she receives that message. In point of fact, with that kind of a laboratory result we did not know in 1985.
So institutions did not inform the donors. They did not use their blood. They did not call them back. The ethics of that, I think, are very controversial. If you do not really know what to tell the donors, what do you tell them? Many institutions elected not to tell them anything.
Harden: Can you describe, to take this one step further, who your donor population is primarily here? Are they NIH or other government employees, or do you have many non-federal people as well?
Klein: We have a very select donor population. For the whole blood part of the operation they are almost exclusively NIH employees. They have a mean educational level of sixteen years. They are interestingly enough equally divided between males and females, which is not what is found across the country. The percentage of ethnic minorities is in keeping with, or slightly higher, than the percentage of ethnic minorities in the regular population. By and large these are repeat donors who have been screened out over the years, some biologically. For example, if a patient develops hepatitis and got blood from one donor only, that donor is removed from the pool. If that one donor is implicated in more than one case of hepatitis, that donor is removed from the pool. So we had a very safe pool of donors and, in fact, only two of the several thousand individuals on our donor rolls were infected with the AIDS virus.
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