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Interview with Dr. Thomas Waldmann
This is an interview with Dr. Thomas Waldmann at the Clinical Center at the National Institutes of Health (NIH), Bethesda, Maryland. The interview was held on March 14, 1990. The interviewers are Dennis Rodrigues, Program Analyst, and Dr. Victoria Harden, Director of the NIH Historical Office.
Rodrigues: Could you tell us about your background and professional experiences; when you came to NIH and what you were doing prior to seeing this patient?
Waldmann: I'm chief of the Metabolism Branch of the National Cancer Institute [NCI]. I came to the NIH in 1956 and have been here for thirty-four years. I started out with an interest in the metabolism of the serum proteins, and I admitted patients to find out how the proteins are catabolized and synthesized.
As part of this endeavor, we were studying the metabolism of immunoglobulin molecules. About twenty-five years ago, I turned to patients predominantly with the genetic, hereditary forms of immunodeficiency, but also to those with certain acquired immunodeficiencies. Obviously, there was a different meaning for the term acquired immunodediciency then. It included those who developed immunodeficiency after a period of normal immune function. Although such patients in that era were rare compared to the AIDS situation now, they were of great educational value.
The genetic errors in metabolic pathways taught us a great deal about the role of various biochemical events in some of these patients with immunodeficiency, and a particular genetic or enviromental error told us a lot about what is important for normal immune function. We learned the ways that abnormal function could occur. We discovered that low levels of immunoglobulins could occur by loss of these proteins into the gastrointestinal tract due to endogenous hypercatabolism as well as by nonsynthesis. An array of diseases such as Wiskott-Aldrich's syndrome, ataxia telangiectasia, common variable hypogammaglobulinemia, and Bruton's agammaglobulinemia were very important in defining not only what makes the immune system work normally, but also the consequences to the patient of immune errors. What is the consequence of not being able to make an antibody? What is the consequence of not being able to have normal numbers of T cells? As part of these studies, we had seen hundreds of patients with different forms of immunodeficiency disease.
We were then informed about a patient in New York who attracted our interest in terms of the possibility of learning more about the immune system. What is common now due to AIDS hadn't been well described then. That is, this patient had been well as a child but subsequently developed profoundly low lymphocyte numbers. We knew profound lymphocytopenia as a genetic congenital error–severe combined immunodeficiency disease, SCID, of infancy–an error in which patients could not make an antibody or cellular immune response. The well-known bubble boy from Texas was such a child. However, in an adult, this had not been well defined or understood.
In this context, we received a referral to the NIH, in June of 1981, of a patient D who, as we shall discuss, turned out to be the first patient seen at NIH with AIDS. To set the stage historically, I believe that the report from the Centers for Disease Control [CDC] concerning five homosexual men with a new immunodeficiency associated with Pneumocystis [carinii] pneumonia [PCP] appeared in the last week of May or the first week of June 1981. But on referral of our patient, that had not been reported. We were not aware of this unreported condition. The patient, unknown to his family, to us, or to the referring physicians, was a thirty-five-year old homosexual man who had been living in New York. He had a particular partner but many other partners as well within the gay community. He had been healthy with the exception of an array of venereal diseases, including syphilis and gonorrhea on a number of occasions, but then he began having lassitude and weakness in February 1981. Weight loss and fever ensued, and he was admitted in April 1981 to the Hartford Hospital where he had Pneumocystis carinii pneumonia, lymphocytopenia, cytomegalovirus [CMV] in the blood and urine, herpes simplex II perianaly, Candida esophagitis, and Mycobacterium avium tuberculosis of the lung, bone marrow, and esophagus. Initially, he was not as ill as you might have suspected from this history. We were presented with an individual who, we felt, would be unable to make T cells.
Harden: Did his physician call you or someone here, or was he in line for a particular protocol? How did the referral work?
Waldmann: Perhaps now would be the time to indicate to you that we do not have the chart available to us anymore. The chart of this patient had been available until the day of his death. But then it has never been seen again. It is conceivable that it was taken for research review by physicians who participated in the patient's care, but it was on the ward where other individuals, the patient's family, for example, might have had access to the chart. The consequence is that I can't refer back to the chart that is unavailable. But unquestionably, we probably had received a call or letter from the hospital caring for the patient. He probably had been admitted onto a protocol, in this case an omnibus Metabolism Branch immunodeficiency disease protocol, 77-C-66 by number. That is a protocol that permits us to do studies on the blood and relatively simple immunological tests on individuals, including those who are healthy as well as those individuals who have recurrent infections, who thus have evidence of an immunodeficiency state. We were aware that the patient had a low level of lymphocytes, the pivotal cellular component of the immune system, and we saw the combination of events that result as a consequence–Mycobacterium avium tuberculosis, Candida esophagitis, cytomegalovirus, and Pneumocystis infection distributed widely. Even in that era before AIDS, one recognized this pattern of infections as the hallmark of a cell-mediated immune defect. If a patient didn't make antibody, we knew he would have trouble with highly pathogenic bacterial diseases such as pneumococcal pneumonia or meningococcal septicemia.
The pattern that we observed in our patient was the kind of pattern one saw in Hodgkin's disease patients who were profoundly anergic, or in patients with a form of profound immunodeficiency called severe combined immunodeficiency of infancy, where the patient cannot make an effective cellular or antibody immune response. What we were seeing was an acquired form of cell-mediated immunity. In the absence of AIDS, this pattern as an isolated event, without cancer, without chemotherapeutic intervention, was an exceedingly rare observation in adults.
Since we wished to look into the cause of this immunological disarray, the patient was transferred to the NIH in June 1981. We were not aware that the report in which the Centers for Disease Control described the five homosexual males with an immunodeficiency was being published during this time. To better understand the problem, when the patient came to NIH, many individuals from the Metabolism Branch joined forces. In my laboratory, for example, we looked at the ability of the patient's cells to make immunoglobulin molecules in vitro in a culture system we had developed in 1974 to study common variable hypogammaglobulinemia. That is another acquired disease whose etiology is undefined, and where some patients have the B-lymphocyte failure and another subgroup has an excessive number of suppressor T cells. This patient could not make immunoglobulins with his cells in tissue culture. These cells in co-culture with my cells inhibited my cells' capacity to make immunoglobulin. Others in the branch studied his cell-mediated immunity. He was unable to make a skin test response to tuberculin, despite the fact that he had widespread Mycobacterium avium, nor could he respond to diphtheria and tetanus antigens to which he had been immunized and to which all the rest of us were responsive. These were the in vivo evidences in this person of a cellular defect.
Beyond that, the ability of his cells to do specific viral killing were determined by [Dr.] David Nelson and others. At a T-cell and at an antibody level, we were defining the functional abnormalities of the immune system that would be reflected in his disease. The patient developed cytomegalovirus retinitis, mycobacteria of the mesentery, and waxing and waning of an array of infections. The Mycobacterium avium couldn't really be controlled as it was not inducing the expected granulomas, but was just growing widely. Many drugs given to him were directed toward the recurrent Pneumocystis, cytomegalopneumonia. He had lung pathology, eye pathology, a history of giardiases, Candida esophagitis and a terrible problem with pain. He had a rectal problem with herpes.
As these features evolved, we drew together a great number of individuals from the NIH community. We were all groping, trying to understand what was going on. In that era, one couldn't be fatalistic, even when someone was in an apparently irreversible state. One had to assume that somehow one might be able to reverse the immunodeficiency and with that bring into control the infectious disease. The Eye Institute [National Eye Institute, NEI] played a major role. They took many pictures of cytomegalovirus retinitis which was unusual to them at that time. Soon the patient moved from the immedicate care of [Dr.] John Misiti, my medical staff fellow who was intensely involved in day-to-day care, to the care of others in the medical intensive care unit, where great efforts were made to treat this patient. The lymphocyte count was profoundly low in the patient, below 1,000 cells per cubic millimeter. The neurological abnormalities became a major problem as the patient became more and more unable to respond, to rationally deal with things. At autopsy we found massive necrosis, encephalitis, and degeneration of the brain.
Harden: After the autopsy, were pathological specimens maintained for later use? Did anybody go back and verify that this was an infection, once the HIV had been defined?
Waldmann: I don't know. With gene amplification by the polymerase chain reaction [PCR], one could do so. We did keep a serum bank in our branch and it would be possible to look back to see if there were antibodies to HIV. We could not do this in 1981, which was before the etiology of this immune deficiency was recognized. We probably did not maintain viably frozen cells although we do so on certain patient groups.
As I was saying, at the end the patient had massive cerebral necrosis and autolysis. We had a great number of people involved in treating all the different systems. You might have to turn to Dr. Misiti to get the names of the individuals. Parenthetically, at autopsy he did have a tumor–not Kaposi’s sarcoma, but a large-cell lymphoma involving the liver. This feature is common today, but at that time it was not easily recognizable. As we groped to explain the immunodeficiency, we recognized that the patient had used many drugs. To us it seemed that any one of these, including amyl nitrite, which was one of the etiological candidates for AIDS at that time, could have been contaminated or otherwise involved with a toxin that might have impaired the immune system.
His disease continued, and the patient finally died on October 28, 1981, of hypotension and respiratory failure, with multisystem involvement. At this time, an autopsy was permitted, and the wide spectrum of infectious diseases was demonstrated. By the time of the autopsy, we recognized that this patient fit into that category of disease that was being described by the Centers for Disease Control.
Harden: Had other AIDS patients been admitted to the NIH Clinical Center by the time he died in October?
Waldmann: We did not see any other cases on our service. The autopsy on our patient says that “This case represents an example of a recently described syndrome of acquired immunodeficiency in previously healthy young male homosexuals,” giving reference there to eight papers. Since one of them is authored by [Dr.] Henry Masur, it might have involved other NIH patients. They viewed this case as having multiple opportunistic infections, especially cytomegalovirus, herpes simplex, Pneumocystis pneumonia. That this case did not have Kaposi's sarcoma, but rather malignant lymphoma was most interesting, and this had not been previously reported. The aspects that were unique to the case at the time were the level of involvement of the eyes, the virtual failure of any response to the Mycobacteriun avium, and the lymphoma, which at that time had not been described in AIDS patients. There were an array of functional assays done, but we do not know the results in the absence of the chart of this patient.
In terms of sociological issues, the impact of this person's disease, on the one hand, and the revelation that he was a homosexual, on the other, had a devastating effect on his relationships to individuals who had been close to him in the past. From the discussions, it appeared that the family was not aware of the fact that while living away from home in New York, he was an active homosexual. This revelation was a very serious blow to the relationship with his family, and a cause for concern not only in terms of immediate interpersonal interactions, but also in terms of the potential impact that this could have on the social milieu and friends of the family.
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