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Harden: In the 1982-83 period, what would you have said to a family member or friend who needed surgery and was anticipating a transfusion?
Klein: I was attending on the service here, so I saw lots of people who required transfusions. And I always told them the risk of hepatitis was substantial–at that time, I believe it was about 10 percent–and I felt that that was substantial, although most of these cases these cases did not develop severe effects. Studies done in this hospital suggested that maybe half of the cases went on to have chronic liver disease, and so that was always the number one concern.
Then I said, “There are a variety of other illnesses that you might get, and most of these are relatively uncommon or relatively unimportant.”
Harden: But you did not see AIDS as a major threat at that time?
Klein: Not in 1982. In 1982 I can tell you unequivocally that I would not have mentioned it. By mid-1983 clearly I was mentioning that AIDS might be transmitted by blood, but that it was a very rare event. I am one of those people who has been castigated ever since for saying “You are probably more likely to be struck by lightning, than you are to have a transfusion-transmitted case of AIDS. We simply don’t see it.” Again, bear in mind that at that period of time there were approximately twelve million units of red blood cells, or whole blood, and another six million units of platelets and plasma being transfused in the United States to some four million people every single year. If you saw twenty cases of AIDS in the United States associated with blood transfusion, they might have had other risk factors but had been transfused anyway.
Many people–four and a half million people–were being transfused, so some of those were gay males, some of them were drug users, some had been born in Haiti or had had sexual contact with Haitians. You could not really say that this was a bloodborne disease, and, if you believed it was, then you still had to say it was not very common. Even if I was only seeing half, or even if I as only seeing one out of ten cases, it was not very common. That is what I was saying in mid-1983. I was saying the risk from blood transfusion was hepatitis, and a person should not get blood if he or she did not need it. But yes, it was conceivable that AIDS was a disease transmitted by blood–very unlikely–but if it was transmitted by blood, it was probably not very common.
Harden: Okay. I interrupted you when you were describing the positive impact of AIDS on transfusion.
Klein: If you look at blood collections in the 1970s and 1980s, you see that they go up about eight percent per year. There were never good data on transfusion, but you can estimate that transfusions were continuing to climb during that period as well, maybe not a percent a year, but all of that blood was not being outdated; it was probably going into human beings. That is why more and more was being collected.
By around 1983-1984, the collections flattened out and, in fact, went down, and now they have flattened out again. The reason is that physicians are transfusing blood much more consciously, really looking for indications it is needed. I would like to think that this was because physicians have become better educated and smarter, but my own feeling, based on no data, is that it was because patients were beginning to ask questions. They were beginning to say, “Is there a risk in this stuff? What is the risk? Will I really need the blood?” And there were lawsuits. There is nothing that the transfusing physician pays more attention to than his legal colleagues or then, in all fairness, his patient who starts to ask questions and brings the issue to a level of consciousness. The patient says, “You shouldn’t transfuse me unless I really need it. I’m scared. Unless I really need the blood, don’t transfuse me.”
So we were beginning to see a much more rational use of blood and blood components. We were beginning to have people say, “Maybe there is something to limiting exposure to donors? Maybe we should think in terms of not exposing people to 1,000 donors if we could expose them to five donors?” You started to see single donor platelet, platelet pheresis, become more prominent. I think that is a safer component for a variety of reasons.
In the mid-1980s you began to see cryoprecipitate that had been collected by blood banks from, say, 16 to 20 donors, being used for hemophilia, or being used for bleeding problems where Factor VIII was an issue, rather than the commercial concentrates which had tens of thousands of donors in the pool. By the mid- or late-1980s, these concentrates were sterilized. So the risk decreased, but at that point in time, the number of donor exposures became a real issue, and physicians tried to limit donor exposures and use less blood. If there is a silver lining to the black cloud of AIDS in the transfusion community, that is probably it.
In addition, many of the history-taking measures that were put in place to limit the risk of AIDS–the questioning about gay activity, and it got to the point very quickly, as it is today, that any male who had sexual contact with any other male since 1977 was not allowed to donate blood–all of those high-risk behavior questions, which are now asked directly of our blood donors, not only limited the risk of HIV and AIDS but clearly were instrumental in decreasing the risk of post-transfusion hepatitis. There is no question about it.
Harden: We have covered the most intense part of the crisis in terms of addressing the ideas of bloodborne transmission and protecting the blood supply. What we have seen in a number of ways is that once a virus is identified the whole process becomes much more rational, that is, when there is something to look at, people focus their studies. Could you comment on how that changed your situation?
Klein: First, I probably should mention that what I believe was the first chimpanzee study was also done at NIH. Again, we had established the chimpanzee breeding colony from the Heart, Lung, and Blood Institute back in the 1970s, and the chimpanzees were available for hepatitis research. When this disease called AIDS came along, it seemed like this might be a way to try to determine whether it was transmitted by blood. The idea, I think, was generated initially by Drs. Harvey Alter and Henry Masur.
What they did, eventually with other collaborators, was to collect components from hospitalized patients in the Clinical Center who had AIDS, or what we called ARC (AIDS-related complex) at the time, pre AIDS. We did not know if they were infectious, or when the infectious period would be. Maybe it was before they got the disease. So, if you just took components from the diseased patients maybe you would miss it and you would not be able to transmit the disease, even though it was transmissible. We also did not know whether the agent was in plasma, or whether it was in cells, or since it was in hemophiliacs, maybe you needed protein concentrates. Maybe you also needed some other factors along with the blood. We really did not know. What Drs. Alter and Masur came up with was to take components from patients in the hospital at different stages of disease. We collected these by apheresis and we made cryoprecipitate concentrates of Factor VIII. We used white cells and plasma. We put together different blood components from different patients at different stages of disease, and then put the result into chimpanzees that were in the colony.
As there was no test for AIDS, the idea was to see: (a) did the chimpanzees get any kind of clinical disease? And then (b) were there surrogate markers, for example, changes in the T helper/suppresser ratio? Was there a decline in helper cells? Those studies were started, I believe, in early 1983.
One of those chimpanzees, luckily for us at the time, developed a clinical syndrome that had never been seen before by the veterinarians– enormously large lymph nodes with were biopsied and were non-specific. The other chimps, I think there were two or three others–and this was published in the Lancet–developed nothing at all. Over a couple of weeks the lymph nodes in the chimp that had become symptomatic went back to normal anyway. None of the chimps got sick. As they were being followed sequentially, their helper cells did go down. By their being followed sequentially into 1984–by that time anti-HTLV-III was discovered–one of the workers in Gallo’s laboratory developed an assay that could be used for chimpanzees. We assayed the chimps which we already thought had been infected with an AIDS agent, and, in fact, they were positive. So were the specimens that had gone into them. The paper that came out showed the clinical syndrome, the reversal of the helper/suppresser ratio, the lowered helper cells and the positive test, although we really knew before the test that something from human beings had been transmitted to animals. That was the first demonstration, I believe, in an animal model that AIDS was a blood-transmitted disease, or that it was a blood-transmitted agent that caused the same immunologic changes in a candidate model as it had in human beings.
The advent of an assay meant that you could now look at donors and look at recipients. In fact, one of the first things that happened when an experimental assay became available was that Harvey Alter went to this freezer and pulled out his post-transfusion hepatitis specimens. He had one of his fellows from Spain, Dr. Juan Esteban, who was here on a Fulbright Fellowship, go through all of them. He found two positive donors confirmed by Western blotting procedures. He looked at the recipients, and these recipients turned positive several weeks to several months after they received the blood. They had been negative prior to transfusion. Those studies, which again were published in the Lancet, defined the window period before positivity for antibody. It was defined from these freezer studies of post-transfusion hepatitis.
Harden: You have now raised another key question. There is a window of time before an infected person tests positive, and the blood supply is therefore not 100 percent safe. Where do we go from here?
Klein: We have managed to narrow the window down. Just to give you an idea, prior to 1985 and the assay, there were over 4,000 cases of transfusion-transmitted HIV. Since the assay there have been 20. We would estimate, based on what we know, that there are maybe 200 infections per year in the United States, maybe slightly less than that. Half of those cases will die from whatever reason they have been transfused for, so there are very few infections. Hepatitis is still a big problem in the United States. There are now, as I said, better assays. The blood supply is better because of the better questioning that we do. If we could use a direct test for the virus...we tried one. We screened 520,000 units of blood with an HIV antigen test. It added nothing. But there is PCR (polymerase chain reaction), which detects the virus. In theory you could detect it within a couple of days of infection and therefore narrow the window of the donors dramatically. But this is not yet a test that can be used for screening purposes.
Harden: Thank you, Dr. Klein. We will continue this interview on another day.
This is a continuation of the interview with Dr. Harvey Klein, begun on 29 January 1993. The date is 8 February 1993. The topic of the interview is the history of AIDS at the NIH. The interviewers are Dr. Victoria A. Harden, Director of the NIH Historical Office and Dennis Rodrigues, Program Analyst.
Rodrigues: The last time that we talked you were telling us about platelet donation procedures that you had implemented I believe that they became standard once AIDS appeared and it was realized there was a greater risk.
Rodrigues: What was the motivation for the original employment of these techniques?
Klein: There were several. First of all we had, as I said I think the last time, about a 30-year interest in post-transfusion hepatitis. This is an interest that goes back to World War II in the federal government when there was a so-called icterogenic plasma. This was plasma that was made by the federal government for use in the war and resulted in large numbers of servicemen developing hepatitis. Back in the 1960s, this particular institution, the Blood Bank at NIH, became interested in post-transfusion hepatitis as “the” major problem with blood transfusion. We were always thinking in terms of infectious risk of blood, specifically of hepatitis, and multiple donors. One of the motivations was to decrease the number of donors for each patient. We believed, although there were few data to support the idea, that if we could decrease the number of donors we would decrease the risk to each patient. That was one reason for getting the largest number of platelets from a single individual.
A second reason was that the NIH began to use more and more platelets because of the kind of population it had. Patients had open heart surgery and patients had cancer. Both of those groups needed platelets. It was very difficult, even if you separated every unit of whole blood into its component parts, to have a reliable source of platelets, because platelets could only be stored for two days. You could store, at that time, red cells for three weeks–this is back in the 1960s and 1970s–and platelets for two days. Unless there was a more frequent source of platelets, red cells would be available but the platelets would be outdated. So we went to the so-called “single donor” platelets for both reasons.
Rodrigues: I have a question concerning an instrument, the IBM 229 separator, which you mentioned when we were talking about AIDS. Apparently someone at NIH collaborated in the development of this instrument. Could you tell us more about that instrument?
Klein: The first continuous flow blood cell separator was developed here at NIH in collaboration with IBM. Dr. Jay Freireich, who was here at the time, developed the NCI–IBM blood cell separator, and the story is an interesting one. It turned out that an engineer from IBM, Dr. George Judson, had a son with leukemia. The child was being taken care of at NIH, and the father came down to see him one time. The two major problems then in supporting kids with leukemia were infection and bleeding. As part of his tour of the facilities the father came through the Blood Bank and saw how blood was collected and separated out in centrifuges. As luck would have it, he had just finished working on a project at the University of Pennsylvania with a heart/lung machine. The heart/lung machine took large volumes of blood and pumped it around the heart and the lungs through an oxygenator in order to make open heart surgery possible. The IBM scientist was familiar with equipment that pumped blood around and oxygenated it. He looked at it and he said, “There ought to be a way that we could hook up a person to one of these machines and separate out the blood components, that is, take what we want and have everything else go back. It looks like all you really need is a centrifuge and a series of pumps similar to the heart/lung machine which used an oxygenator and a series of pumps.”
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