ORAL HISTORY PROJECT

Jerome O. Klein, MD

Interviewed by Stanford T. Shulman, MD

April 29, 2012 Boston, Massachusetts

2014 American Academy of Pediatrics Elk Grove Village, IL

Jerome O. Klein, MD Interviewed by Stanford T. Shulman, MD

Preface i About the Interviewer ii Interview of Jerome O. Klein, MD 1 Index of Interview 25 Curriculum Vita, Jerome O. Klein, MD 27

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PREFACE Oral history has its roots in the sharing of stories which has occurred throughout the centuries. It is a primary source of historical data, gathering information from living individuals via recorded interviews. Outstanding pediatricians and other leaders in child health care are being interviewed as part of the Oral History Project at the Pediatric History Center of the American Academy of Pediatrics. Under the direction of the Historical Archives Advisory Committee, its purpose is to record and preserve the recollections of those who have made important contributions to the advancement of the health care of children through the collection of spoken memories and personal narrations. This volume is the written record of one oral history interview. The reader is reminded that this is a verbatim transcript of spoken rather than written prose. It is intended to supplement other available sources of information about the individuals, organizations, institutions, and events that are discussed. The use of face-to-face interviews provides a unique opportunity to capture a firsthand, eyewitness account of events in an interactive session. Its importance lies less in the recitation of facts, names, and dates than in the interpretation of these by the speaker. Historical Archives Advisory Committee, 2014/2015 Jeffrey P. Baker, MD, FAAP, Chair Lawrence M. Gartner, MD, FAAP Jacqueline A. Noonan, MD, FAAP Howard A. Pearson, MD, FAAP Tonse N. K. Raju, MD, FAAP Stanford T. Shulman, MD, FAAP James E. Strain, MD, FAAP

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ABOUT THE INTERVIEWER

Stanford T. Shulman, MD Dr. Shulman is Virginia H. Rogers Professor of Pediatric Infectious Diseases at Northwestern University, Feinberg School of Medicine and Chief, Division of Infectious Diseases; Chairman, Infection Control Committee; Medical Director, Microbiology Laboratory at Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL. His major academic interests are Kawasaki Disease, group A streptococcal infections, and the history of medicine. Dr. Shulman graduated from the University of Cincinnati and from the University of Chicago Medical School, was resident and chief resident in pediatrics at the University of Chicago, received additional training at the Institute for Child Health in London, England and was a fellow in Pediatric Infectious Diseases and Immunology at the University of Florida College of Medicine. Dr. Shulman is board-certified in Pediatrics and Pediatric Infectious Diseases. He is past Chair of the Section of Infectious Diseases of the American Academy of Pediatrics; Dr. Shulman is past President of the Pediatric Infectious Diseases Society. Dr. Shulman was a long-standing member of the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, and twice served as Chair of that committee. He was also a board member for the World Society for Pediatric Infectious Diseases. In 2014 Dr. Shulman received the Distinguished Physician Award of the Pediatric Infectious Disease Society. Dr. Shulman has been a visiting professor and invited speaker nationally and internationally and has authored over 250 peer-reviewed publications, over 60 book chapters and has edited or co-authored six books in the area of infectious diseases. Dr. Shulman serves as Associate Editor of the Journal of the Pediatric Infectious Diseases Society and is Editor-in-Chief of Pediatric Annals. He is a congenital Detroit Tiger fan and an adopted Chicago Bulls fan.

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Interview of Dr. Jerome O. Klein

DR. SHULMAN: This is an interview of Dr. Jerome O. Klein, conducted by Dr. Stanford Shulman, on April 29th, 2012, in Boston, Massachusetts. Jerry, thank you for agreeing to be interviewed today. Can we start out by your telling me something about your family background, where you grew up, your parents, your siblings? DR. KLEIN: I grew up in the Bronx. It was a middle class neighborhood in the 1930s and 1940s, but it was a very secure neighborhood, and I felt very comfortable in primary school and junior high school, and then I had a lucky break. I passed a test to get into the Bronx High School of Science, which in retrospect was the most demanding academic atmosphere I have ever participated in. It was rigorous. The writing was fastidiously monitored. You really learned a lot that prepared you for college, and many of my classmates went on to have significant careers. Interesting to me, not that many in medicine, but a lot in science, a lot in politics, and a lot in business. One of my classmates was Stanley Plotkin, who has been illustrious in developing vaccines and a star in pediatric infectious diseases. But it was that kind of middle class kids who aspired to -- by education and by learning the basics -- to be productive citizens. After high school, I can’t remember how I chose a college. I had an uncle who was a professor of economics at Brooklyn College, and he guided me, but I think I applied to a few schools that were sort of disparate, like University of North Carolina, University of Cincinnati, and I don’t know why I applied there, but I was accepted and went to Union College in Schenectady, New York. DR. SHULMAN: Before we get to college, can, can you tell me something about your family? DR. KLEIN: I was very fortunate. I was an only child, and I had a father who was ethical, insightful, understanding. I aspire to be as good a person as he was. I had a mother who doted on me as an only child, and it was a loving family that gave me a feeling that whatever I wanted, whatever I touched, I could succeed. You had to work hard, but you still were going to be able to achieve your aspirations. DR. SHULMAN: Jerry, can you tell me your parents’ occupations? That’s the one piece that I don’t think we have. DR. KLEIN: My father was a junior executive in a wholesale button company in the Garment District in New York City. And at the time the garment industry employed 20% of all employees in New York City. It was a dominant force. This was the 1930s through the 1960s. Since then the world has changed, and I think the garment industry now in New York City employs about 3%, rather than the 20% that it did in the 1930s. My father traveled to places where there might be costume jewelry and pearl materials that would be available for buttons, such as along the Mississippi River, in Muscatine, Iowa, and invariably bring me back some souvenir from those areas. My mother was a homemaker,

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and at the time this was the usual arrangement. But she was a caring mother who went to great lengths to provide interesting meals, and a loving person. DR. SHULMAN: I have noticed that, Jerry, you have an interesting or unusual middle name, which is Osias, O-S-I-A-S. Is there a story there? DR. KLEIN: Very little. It was my grandfather’s name, and it has actually been very useful to me, because in medicine but other professions, too, there are other Jerry Kleins. There are even some Jerome Kleins. But to have O as your middle initial and then a distinctive middle name representing the O has been helpful in making myself separate. So there are a few J.O. Kleins in the medical literature, but not too many Jerome Osias Kleins. DR. SHULMAN: Thank you. Can you recall any childhood events that influenced your career choice? DR. KLEIN: There were some physicians I knew, one in particular who was my primary care physician, whose name was Morris Greenberg. Morris Greenberg, while having a complete pediatric practice, had an office in the ‘80s in New York City, in Manhattan, but would make house calls. And, you know, to make a house call from the ‘80s to where we lived on 172nd Street in the Bronx, he’d have to get on a train, then switch to a trolley, then walk several blocks, and it may be that a house call was $5 at the time, so I can’t imagine how this was a financially lucrative business. But he had a family. One of his sons, Daniel Greenberg, became a recognized science writer, and has frequent editorials in Science Magazine. But as I found later, Morris was also the Director of the Bureau of Preventable Diseases for the City of New York. DR. SHULMAN: Wow. DR. KLEIN: So while having a full-time pediatric practice, he also was responsible for policy for the Bureau of Preventable Diseases. This became known to me first during an experience with smallpox. It must have been about 1947; I think I was still in high school. There were several individuals who had traveled from Mexico to New York City, and during that 3 or 4 day bus trip they developed pustules that on arriving in New York and going to Bellevue Hospital were diagnosed as smallpox. What followed was an all-out effort to vaccinate 6 million New Yorkers. Now, it’s been criticized subsequently that there could have been a different management plan, in terms of cohorting the patients and mode of immunization. DR. SHULMAN: That this might’ve been a marked overreaction, if you will? DR. KLEIN: And if you think about 6 million individuals without recognition of what their immune status was, there were undoubtedly eczema vaccinatum and other adverse events that occurred. But this was Morris Greenberg using his skills to put together that historical plan that may have many critics subsequently. And later, as I became a physician and then served my obligatory military service at the [US] Centers for

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Disease Control in the Epidemic Intelligence Service [EIS], Morris helped me, because I wasn’t sure whether there was a role that I wanted to fulfill, to emulate what he had done, being a practitioner, and also being a player in the public health system of a large city. DR. SHULMAN: So how did you become interested in medicine? Was it as a consequence of your interactions with Dr. Greenberg, your pediatrician? Or were there other influences, do you think? First your interest in medicine, and then your interest in pediatrics, and then ultimately your interest in infectious diseases. DR. KLEIN: Well, the first question about -- how do you decide to go into medicine? I think that it must have been some vague idea of how you could be as important in the health of individuals who were around you. I think it’s sort of an amorphous sense, and I’m not sure of any seminal event that stimulated me to go into medicine. But I think I always felt comfortable that that’s what I wanted to do. In college, I wanted as full an experience as possible. I was a history major, so I took the minimum of the sciences that were required for medical school, but I loved all the other courses, including history of the Middle Ages, American history, and the various other humanities that were available to me. And Union College was a terrific place to have that education, in that it was small. I think there were about 400 in each class. You could do whatever you wanted. If you wanted to be on the lacrosse team you could try out for the lacrosse team, and I did, and I was beat up, and decided that probably wasn’t the sport for me. If you wanted to be on the newspaper, the Concordiensis, you could be a reporter, and then if you were really good you might get up to the associate editor, or editor. I was never that good, so I stayed as a reporter. If you wanted to have a program on the radio station, WRUC, you could pick your time, if it was available, and your subject, and I did. I had a program on Friday nights called Broadway Melody, and I chose songs that I was familiar with and that were in the library at the radio station from Broadway shows. My theme song was Cole Porter’s You Do Something to Me and while the microphone was on mute I would sing along with the recordings. I still do that. I was in college from 1948 to 1952, and you have this huge library of materials from the 1920s, 1930s, 1940s, and I was enthralled by it. During that period, living in New York City, I would see every show that was on Broadway by standing. So if you had a popular show that opened, such as, say, Kiss Me Kate or South Pacific, for $1.50 you could go and stand right behind the orchestra, so it was a terrific viewing opportunity. You could see everything that you wanted. And I think the pinnacle was on one day—it must have been in the spring of 1949 – that I saw Death of a Salesman in the afternoon, at a matinee, and South Pacific at night. You can’t do much better than that in terms of a theatrical experience. But the interesting thing is I’ve saved every playbill from that time, and now I have some bound volumes. As plays are revived it’s interesting to go back and see who was in the original and the remembrance of that extraordinary experience of seeing live theater, and then the opportunity when I was in college to play all the songs that were very important to me. DR. SHULMAN: Of course, we have a revival currently of Death of a Salesman that I recently saw with Philip Seymour Hoffman, but no songs that relate to that.

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DR. KLEIN: No, but what an extraordinary dramatic experience. I saw Brian Dennehy in Chicago at the Steppenwolf, and then again in a road company in Boston, and it’s like Greek tragedy. This play will be put on by our grandchildren and great grandchildren, and it has themes that are important to all of us about the struggle of middle class individuals for professions that are becoming less important than they were. Important to me was the father/son relationship in Death of a Salesman, and the supportive care of the mother. DR. SHULMAN: Yes. With your interests as you’ve detailed them, it seemed to me that you might have had a lot of potential career paths. Did you struggle with that decision about going to medical school? DR. KLEIN: No, I really felt comfortable that that was the only thing that I wanted to do. But along the lines of your question, I’ve always felt that in medicine we’re participating in theater, even in our relationships. Some of them are father/son relationships—we’ll talk later about my relationship with Maxwell Finland. Also, our approach to the crises that occur, the various events that occur, in the emergency room, on the floors, in the intensive care unit, and how as you reflect on your role and the various events that have occurred, how much of this is theater. And hopefully you play your role: supportive, and being a caregiver, that is valued by your patients. DR. SHULMAN: So you decided to go medical school, and you go to Yale [School of Medicine]. I’m interested in what you can tell us about your experience as a medical student at Yale, and, as part of that, how pediatrics became your choice. DR. KLEIN: The choice of Yale was terrific. I really enjoyed my experience of the medical school. But I have to tell you first about how Yale dealt with interviews for their candidates. I had a very good college record, and I had done some extracurricular activities that I’ve mentioned, relatively modest. But it was December of 1951 -- because I graduated college 1952. So it’s December 1951 that I go for my interview. And I’m interviewed by the Dean of Admissions, whose name was Tom [Thomas R.] Forbes. He was very kindly. He was a fatherly figure to interviewees. And I’m sent to the head of the Department of Biochemistry, who grilled me, and sort of demeaned everything that I said, and I felt that that’s probably the kiss of death for admission to that school. I was to come back to Dean Forbes for any final instructions before I left. And he sat me down and said, “I’m pleased to offer you a place in the class that begins in September 1952.” Well, it was thrilling to have that kind of approach that immediately gave the student a feeling of being accepted and being there, and particularly after a tough interview in biochemistry. So that was one of the thrilling points in my life, when all of a sudden somebody says something that is going to change the pathway that you have in medicine. So that September I began Yale, and I find that having been a history major I’m not as well tuned in terms of some of the areas that my classmates are really up on. Biochemistry—I took the minimum—was tough going. But Yale had this wonderful system, that they still have to this day, that all tests are voluntary, and you self-mark your tests. The only demand is you pass the Boards at the end of the second and fourth years.

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So I felt relatively comfortable that I could catch up with my more knowledgeable classmates. In fact, for the first 2 years I never felt that I caught up. I always thought they were smarter than I was. But as you get into the clinical years, it’s like all that stuff is prologue, and all of a sudden you’re on the wards, and you’re dealing with patients who have a history, and you’re doing an examination, and the Krebs cycle isn’t as important as it was during the first year or 2, and other minutia of biochemistry. So I was catapulted from being what I think was a mediocre medical student in the first 2 years to really latching on and feeling comfortable that I could be a very good clinician in the third and fourth years. Now, my first clinical rotation was at the VA [Veterans Administration] Hospital in West Haven, Connecticut on the surgical service. The surgeons didn’t pay much attention to the students. They were smart, somewhat arrogant. The patients at the VA Hospital were often alcoholic, cirrhotic, syphilitic, not ones that you could really have a lot of empathy for, as much as you were a medical student you wanted to care for them. So I crossed surgery off my list of potential vocations. Next, I had a rotation on medicine, and medicine was 180 degrees different. But even there, there were large patients, obese patients, ones that I didn’t feel I wanted to spend a lifetime percussing a chest of a 250-pound elder. And then I went on to pediatrics, and pediatrics had a faculty that was extraordinarily tuned in to the students, very caring in terms of how they presented the education on the pediatric service. Milton [J. E.] Senn was the chair of the department, but there were other luminaries, like Bob [Robert E.] Cooke, who went on to be the chair at [Johns] Hopkins [University School of Medicine], and Morris Green, who was to be a star and has written many textbooks and had a long career at Indiana [University] School of Medicine. And these people were role models. They were the ones that I felt most comfortable in being around and wanting to emulate. So pediatrics became what I wanted. Also, I enjoyed taking care of children. So your choice is based on some abstract that you’re not entirely sure about, but you know it when you see it. It’s like love. You have a woman that you find some emotional relationship with, and you know what it is. And I think it is the same thing when you choose the area of medicine that you like. So I became focused on pediatrics as the choice for my career. DR. SHULMAN: So you spent your whole life to this point on the East Coast, and you’ve now chosen pediatrics, and you wind up in the cold north country of Minnesota. How did that happen? Tell us a little bit about that. DR. KLEIN: Because of the qualities of the department of pediatrics, there were a lot of the members of my class who wanted to go into pediatrics, and most wanted to stay at Yale, as I did. There were about 12 of us. We knew they had an internship class of about 12, but they’d only take 2 or 3 from Yale. So each of us started looking elsewhere. I looked at a number of programs, and one of them I had read a lot about. Some members of that department, pediatrics and the infectious disease division, such as Lou [Lewis W.] Wannamaker and Bob [Robert A.] in Minnesota, so I decided to have an interview there. They welcomed me with outstretched arms, and made me feel so comfortable that I felt that that was a place I wanted to be.

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As it turned out, of the 12 members of my class that wanted to go into pediatrics, none of them went to Yale. They all felt that they had to look elsewhere, because Yale would not accept more than 2 or 3, and it turned out that none of us went to Yale. You know, I didn’t mention some of the other people at Yale who were important role models, including Bill [William L.] Nyhan -- who subsequently goes to San Diego, and is responsible for identifying the Lesch-Nyhan syndrome. Well, Bill was a chief resident when I was a medical student. So it was a wonderful atmosphere, and it catapulted me into a pediatric program at the university hospital in Minnesota. DR. SHULMAN: And were you already interested in infectious diseases at the time you left Yale? Had that already become a love? Because you mentioned Lou Wannamaker at Minnesota. DR. KLEIN: Yes. I think I felt that the world was your oyster, and you could make many choices, but the people who were associated with infectious diseases at Yale were, again, role models, people like Dorothy [M.] Horstmann, John [Rodman] Paul, who were so important in the developmental biology of polio viruses and the steps that were necessary to go on to develop the vaccine. Joseph [L.] Melnick was another virologist who gave terrible lectures. I’d looked forward to them in second year microbiology, and as I found with some of my subsequent mentors, they’re not always the best lecturers. Joe Melnick had a lot of interesting material to present, but he was not the actor as lecturer that I would have hoped for. But he still was important in the infectious diseases realm. What was interesting to me as I look back is that there were no infectious disease consultations. Dorothy Horstmann might come to give a lecture as part of the pediatric program, but she rarely saw a patient on the pediatric wards, and I think it was an era when there was a lot of infectious disease, and you expected that everybody would be knowledgeable about management. So it’ll come in our story as it develops later that this is where infectious disease, important enough in the general care of children, was such that each pediatrician was expected to be his own expert. DR. SHULMAN: So you emphasized how mediocre a student you were in the first couple of years of medical school, but I notice that you were AOA [Alpha Omega Alpha], and you commented on how you felt that when you hit the wards, your performance picked up. Is it fair to say that it phenomenally picked up because of your other qualities in terms of empathy and ability to interact with patients? DR. KLEIN: Well, I think there’s such a qualitatively different experience in, at the time, lectures and learning the components of the Complement cascade and other minutia of the preclinical years, and then all of a sudden the juices that flow into the areas that you really are excited by become available in the clinical years. What a year, as a student on obstetrics, to be in the delivery room and catch the first baby, or to take care of kids later who have polio or other infectious diseases. So I think it sort of draws you. It’s a magnet that brings you to a love of being a caretaker, and being able to relieve the burden that some kids have of, in my interest, infectious diseases. But it certainly was a point of decision in going to Minnesota and looking at Lou Wannamaker and Bob Good as not only

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being stars but being very interested in their students, and how they wanted to impart to you, as the student, the knowledge that they had. DR. SHULMAN: So how was that year in Minnesota? You just began to touch on that. And, and you didn’t stay there very long. DR. KLEIN: It was cold! (Laughter) But my wife, Linda, was taking a Master’s at the university. She would drop me at the hospital in the morning, and go on and park the car and walk across campus to the classrooms, so I never felt the cold. But it was a consultant hospital for all of Minnesota, the Dakotas, and you saw disease that was varied, and interesting, and tough. I think being an intern, and being on, say, from Saturday morning through to Monday night was challenging. By the time I got home Monday night I felt exhausted, but that was the way you saw the complete portrayal of an illness. One of the first patients I had was a child from northern Minnesota who came in with a large number of black bullae, temperature 104, must’ve been a 2-year-old, and I’m new to Minnesota. I said, “What kind of bizarre illnesses are coming from northern Minnesota? Are there some zoonoses that are special to that part of the country?” And as we did a gram stain on the fluid in the bullous lesions, it was chockfull of polys and gram positive cocci in clumps. This kid had overwhelming staphylococcal sepsis and died. But there are cases like that, that are so traumatic in your recall of the way the child presented that it remains with you forever. It’s like an infant born on a farm whose father comes in from the barn to cut the cord and the infant goes on to have neonatal tetanus. I’d never taken care of such a child before or after, but what a challenge it is to sustain a child who is having tetanic seizures. Minnesota was a magnet for that type of important disease throughout that part of the Midwest. DR. SHULMAN: At what point in your education did you meet Linda? DR. KLEIN: Linda and I met on a blind date when she was a junior in high school and I was a third-year college student, and it was love at first sight. And it’s one of those things like choosing your profession: you know it when you see it. And it doesn’t mean that aren’t years in between where there’s some highs and lows, but we decided that we would get married after my second year in medical school. So we’ve been married -- it’ll be 57 years this June. It feels like yesterday. But we’ve had a wonderful symbiotic, loving relationship with 3 terrific kids, who all live in the Boston area, so we’re blessed in having our 3 children and 3 grandchildren all being close by. DR. SHULMAN: Even if you have to put up with the Red Sox. I’m just kidding. [Laughter] DR. KLEIN: Well, we should talk about the Red Sox at some point, Stan, because they’re an important part of my emotional makeup. There are ups and downs, and it’s a real phenomenon. You know, I’d never thought that fans were more than people who went through the turnstiles, but in Boston it’s different. And I find psychologically that if they win, like they won last night, 1 to 0, you feel good; if they lose 1 to 0, you don’t feel so good.

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So there’s a communal experience. And the fact that my kids are all big fans, my grandchildren are all big fans gives us the family experience, as well. DR. SHULMAN: I will say that that’s not unique to Boston and to the Red Sox, but we’ll talk about that another time. DR. KLEIN: I’ve heard it said that it happens in Detroit, also. DR. SHULMAN: Yes, correct. After a year in Minnesota you moved on. DR. KLEIN: Well, let me talk a little bit more about Minnesota. DR. SHULMAN: Yes, please do. DR. KLEIN: One of the most impressive figures there was Bob Good, and at first I resented him somewhat, because every patient that came in you had to put a vial of blood aside for Bob Good. You identified the patient’s name, the diagnosis, the date. So, you know, if you had a small infant, you’re struggling to get into a hair of a vein, you might or might not be sympathetic to the idea of taking out blood for Dr. Good. But as I got to know him, he was an extraordinary individual. He came from a large Minnesota farm family. One of his brothers was also a physician. He had had polio as a teenager, and he had a limp. But we would go on rounds, and he knew the textbook of pediatrics. If you had a child with a retinoblastoma, and you had just looked up Nelson’s Pediatrics for retinoblastoma, Bob would give you the encyclopedia, not just the paragraph. Extraordinary mind, and an extraordinarily good person, very sympathetic. Later on, when I presented my first paper at a pediatric meeting—and I can’t remember what it was; I think it was a relatively modest contribution—Bob came up to me afterwards and said, “Jerry, that was a wonderful piece of work. I’m really proud of you.” And I exploded. I called my wife right away. “Bob Good was in the audience and thought that I had done well.” Later on, Bob Good has a story that doesn’t end as well as I would hope for him, because he had the potential to be a Nobel Prize winner. He had done work that distinguished B-cells from T-cells, the importance of the thymus and other immunologic organs, and he was chosen to be the head of the Sloan-Kettering Institute in New York City. He had an experience that I think teaches all of us how careful to be about monitoring our fellows, colleagues. It turns out that there was a paper presented called, “The Painted Mouse,” describing a transplant of skin from a black mouse to a white mouse. I don’t remember the specifics of why this was an important immunologic breakthrough, but obviously the fact that the skin transplant was not rejected by the recipient mouse was the core issue. Well, it turned out that the fellow, whose name was [William] Summerland, had painted the black patch on the recipient mouse, and the paper subsequently had to be retracted. It brought some ignominy to the institution. Bob subsequently resigned, and became head of pediatrics in, I think, St. Petersburg, Florida [University of South Florida]. But he never got the Nobel Prize. He never got the acclaim that he deserved.

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I think it points out to all of us in academic medicine, as we tutor and are mentors to our young people, how carefully we have to review the results of their research, and how critically we have to look after every detail, because if your name is on the paper, you’re responsible. It also points out, in an era where we’ve seen a number of fraud issues in science, that if it is totally misguided biologic science will out. If you find something and it is biologically true, truth will be corroborated. If it is a falsehood, it won’t be and it’ll fall by the wayside. So why young people, or even people who have had some experience, would try to perpetuate a fraud in science is so misguided that I think there’s just some personality quirk that led them down that trail. But Bob was an iconic figure in pediatrics, and received a lot of awards, but perhaps ended his career without the stature that he deserved. DR. SHULMAN: Thank you. That’s a great summary of an extremely important topic. So moving on, again, you don’t stay in Minnesota long. You decide to go in a slightly different direction. DR. KLEIN: No, actually, it was in the same direction, but at the time there was obligatory military service, and I looked around for something that would serve my interests as best it could. I came upon a brochure about the [CDC] Epidemic Intelligence Service, which sounded interesting, but I didn’t know much about it. What I learned was that this was a small group that had been started about 5 years earlier, so right now I’m finishing my internship in the June of 1957, and in that winter I’m looking for opportunities to fulfill my service obligation. And there was a fellow named Alexander [D.] Langmuir who had started this program where young people, interns and residents in medicine, would be participants in a program that would be available if there were epidemics or other public health problems that occurred, not only in the United States, but overseas as well. And it sounded like something that would be exciting, and not, perhaps, the humdrum that might occur if you were stationed at a base on a military installation. And it was. I was interviewed in Minnesota. One of Alex’s lieutenants, Donald A. Henderson, came to interview me. D. A. had a particular approach, a persona that was very authoritative. We had breakfast together, and he said to me, “Jerry, you know this is a very important program. Are you up to it?” Now, at this point I didn’t know a lot about the program, so I said yes to anything D.A. asked. And he said, “Do you think you have the qualifications for this important national program?” I said, “Yes.” There were a number of other questions that D. A. had. I think I had all the right answers, because I said yes to everything. [Laughter] But I was chosen. There were 12 of us who were in that class, beginning in July of 1957. We had a 6-week indoctrination program at CDC [Centers for Disease Control] before we were sent out to our various assignments. Now, Alex Langmuir was one of the most important people in public health in the past 50, 60 years and, again, I think he has not received the recognition that he should. Today, the EIS, the Epidemic Intelligence Service recruits about 60 physicians and other health care professionals, all of who are being trained in epidemiology, not only of infectious diseases but non-infectious diseases. They will then perpetuate the lessons that they’ve learned as

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they go on to work in the areas of epidemiology and public health. They are populating our schools, not only in the United States but overseas. So this was Alex’s baby, and he ran it in an authoritative way. He was a commanding figure who was one of the important people in the lives of those who were brought into the EIS program. But Alex, because of the number of people that he trained and who then went on to academia and state public health programs. I think it has made a huge contribution to the welfare of the American public health. My assignment was at the New York State Department of Health, in Albany. The first assignment I had, first outbreak, was Asian flu at a summer camp in Lake Placid, New York. You went up, you did the usual epidemiologic workup of how many kids were sick, who their contacts were, what the incubation period was, the attack profile, attack rate profile, and it was fun. Subsequently, there was a continuing outbreak of influenza. It went through the state, and there was concurrent endemicity of Staph. aureus. We had a lot of people who had antecedent influenza infection and were dying of Staph pneumonias. So it was a tough period, but a very interesting one from a standpoint of an enterprising young epidemiologist. I learned a lot about New York State. One of the early experiences was a call from Atlanta regarding 3 butchers in Jamestown, New York who had pustules, and the local hospital had diagnosed them, for reasons unknown, as anthrax. So Stan Plotkin and I go to Jamestown to investigate this exotic infectious disease. DR. SHULMAN: He was also an EIS officer with you? DR. KLEIN: Stan Plotkin was in the EIS class with me, and he and I are assigned to go to Jamestown, New York to see what’s up with these 3 butchers. We arrive on a Friday afternoon. These guys had hands with substantial pustules that looked like staph pustules. So we did a gram stain, and it was polys, and gram-positive cocci in clusters, again. It was clear within the time to do a gram stain that these guys didn’t have anthrax; they had staphylococcal pustulosis, and they probably spread it among themselves. So we called Atlanta and told them anthrax was not a concern. This was staph pustulosis. Now can we go home? And they said, “No, you have to stay and make sure the clinical course is consistent with [laughter] staphylococcal pustulosis.” So we stayed in Jamestown, New York for the weekend. Now, Jamestown, New York for the weekend was not a place where there was a lot to do. I forgot what Stan and I did beside eat, but I remember we watched the Miss America contest. That was the highlight of our weekend [laughter] in Jamestown, New York. There were a number of outbreaks which were essentially scares, and they turned out not to be the concern that the local health official had. But I spent 2 years in Albany, New York. Albany is not a bustling entertaining center, but around it there is. The Berkshires are there. New York City isn’t too far away. But as was true with many of my married EIS officers, 2 years in Albany, 2 children, and so that was a wonderful period for Linda and me, and I learned a lot. The people in the state health department were very professional. The head of the division was a gentleman named Bob [Robert M.] Albrecht, and he became one of my father figures, as well. But I wanted more clinical work, so I

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clearly was not going to stay in a public health service area, unless it included a substantial clinical component. DR. SHULMAN: Tell us, Jerry, why did you only spend a year in Minnesota? DR. KLEIN: Well, in fact, Linda and I had every intention of returning to Minnesota after my obligatory service, and I had signed up to go back. We loved Minneapolis. The people were very warm. The medical school was extraordinary. There were still people in my area of interest like Paul [G.] Quie, who had come back from the Navy to join with Lou Wannamaker and Bob Good. Gerry [Gerold L.] Schiebler was a resident when I was an intern. It was a place that I loved. But after the birth of our first child we had a vacation on Cape Cod, and it was a rainy day, and we drove in to Boston, and looked around, and said, “You know, we could come to Boston for a year, and then go back to Minnesota,” because it’s a long life ahead of you. Why not spend a few years in this mecca of medical expertise and bring that back to Minnesota? So, in fact, we did that. But Linda’s responsible in large part, because I had an interview with the Boston City Hospital, where the chair was Sydney [S.] Gellis, who was a mythical figure in pediatrics as a super clinician. I enjoyed the interview I had with him. He was really a very warm person who I enjoyed very much in the interview. But the place was a dump, and as I walked through the halls I said to Linda, “This is not like the ivory tower of the Mayo building on the banks of the Mississippi River in Minneapolis.” And she said, “I don’t think it’s so bad, and I think we could be very happy here, that you would enjoy it, and we could have a good year in Boston before our return to Minneapolis.” So I said, “You’re probably right.” That was the start. So 1959 I arrived as a second-year resident, and that’s 1959, so this is 2012. I never left that hospital that was, and still is, a community hospital for about 40,000 children, and I’ve been able to feel comfortable and gratified by my experience over these now 53 years. DR. SHULMAN: So you’re there in Boston as a second- and third-year pediatric resident. Did your interest in infectious diseases really grow during that time? DR. KLEIN: Not only did it grow, but Sydney Gellis was such an insightful person that he said, “How would you like to take some time with Max [Maxwell] Finland?” This is while I’m a pediatric resident. I knew of Max Finland as, again, a mythic figure, a giant in his field. Sydney arranged for me to spend 4 months in the virus laboratory with Marty [A. Martin] Lerner. It was a time when the enterovirus area of investigation was bursting. There were still cases of polio in Boston. And I had a wonderful experience. Max couldn’t be nicer. Now, when you say Max couldn’t be nicer, Max was extraordinarily reserved, so he wasn’t one to put his arm around you and say, “You’re doing a great job, Jerry.” But he was one who would say, “I hope you’ll apply for a fellowship after you finish your pediatric residency,” which I did. I was accepted to what has been a band of brothers and sisters. Max had about 112 fellows, beginning with Harry [F.] Dowling, in 1936 through John [E.] McGowan [Jr.] in 1972, and he was a selfless individual. He gave of himself to his fellows, both by his knowledge, by promoting their progress, getting them jobs, hearing them out when they

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would have difficulty in their new jobs. And they felt an extraordinary bond among themselves, as well as to him, so that it was really a group of brothers and sisters who felt that common experience of learning, but also the attachment to this unique individual. In 2002, to celebrate the centenary of his birth, we had a big reunion with a scientific program, and more than 100 of his living fellows came back to be among each other, and to celebrate this individual who had meant so much to our professional careers. DR. SHULMAN: Tell us about the pediatric subset of those 112 fellows, and also tell us a bit about Maxwell’s personal life. DR. KLEIN: Well, I’ll start with his personal life. Max had been born in Russia, and came to this country when he was about 5 years old, and lived in what was then a Jewish area in Boston, Roxbury. He got into Harvard College at a time when not too many Jewish kids were getting into college. He had a newsboy scholarship that was able to pay his tuition. Then he got into Harvard Medical School, which I think, again, was fairly restricted. After graduating from Harvard Medical School, he was a resident at the [Boston] City Hospital. That begins 1928. He starts work on pneumonias, and pneumococcal disease in general. The chief of infectious –disease—and I think there was not a division of infectious diseases at the –time—was Chester [S.] Keefer. And Chester Keefer became an important person in infectious disease during World War II. During World War II, Chester Keefer had been the czar of penicillin. He controlled the small amounts of penicillin that were available for the civilian population. But then Chester Keefer went to Boston University to be dean, and an important person there, and Max became the dominant infectious disease person. This was at the Thorndike Memorial Laboratory. The Thorndike was the first research laboratory that was supported by a municipality, and the first director of the Thorndike was George [R.] Minot. George Minot had won the Nobel Prize for his studies of pernicious anemia, and it sort of set the academic threshold for what was expected of people who came to the Thorndike Memorial Laboratory. When I was there, the head of hematology was William [B.] Castle, who was renowned for Castle factor, an important part of the pernicious anemia story, and Max was the director of infectious diseases. He had no juniors, but he took 3 or 4 fellows each year, and the fellows stayed on for 2 or 3 years. So there was a pyramid with Max at the top, and everybody else filling the bottom. When I started my fellowship with him in 1961 there was a burst of new penicillins. You recall that Beecham [Research] Laboratories [Ltd.] had been able to separate the penicillin nucleus, and they were able, by a semi-synthetic process, to attach side chains that made 500-600 new penicillins. It was a time when staphylococcal disease and multi-resistant staph was an important concern, and all of a sudden we had methicillin, and then oxacillin, and nafcillin as these semi-synthetic products were effective against the penicillin-resistant Staph. aureus. Max was the conduit for most of the important studies of the pharmacology and the clinical studies of these new penicillins.

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As I recall, as fellows we went out with a small box that included the experimental penicillins. P12 was oxacillin. P25 was ampicillin. They didn’t have names yet. And if there was a patient who had staphylococcal pneumonia, you gave him P12, and they usually did well. I don’t think there was informed consent [laughter] at that time. We just gave what we thought was an important remedy for their disease, and it usually worked. And we published a number of papers on both the in vitro activity, as well as the pharmacology, and the clinical studies. It was also a time when I was interested in the virus laboratory with Marty Lerner, and we published a number of papers on the different manifestations of coxsackie and echoviruses. It was fun. Growing tissue cultures, seeing the cytopathic effects that were evident, neutralizing them with the various antibodies to identify the specific virus was a good experience. Max was 24/7. He was there all the time. We would be expected to be there through Saturday. DR. SHULMAN: Tell us where he lived. DR. KLEIN: Max had a home in Squantum, which is in the south of Massachusetts, but he rarely used it. He lived at the hospital. If you were up early, you’d see Max in the dining room having breakfast at 6 o’clock in the morning. You might have seen a patient at 5:00 a.m. when you were struggling in. Max was starting his day, and he was in his laboratory and his office until late hours of the night. So he was a 24/7 person. But many of us might have been, you know, 24/6. We weren’t as complete, but it certainly was a different atmosphere than is present today where the residents are obligated to go home, and Saturday grand rounds is of historical interest only. Max couldn’t be a more supportive individual, but he was also a very good critic. If you had a proposal for a study, he would point out the flaws and say, “You’ll never get enough patients to get a sample size that is adequate,” or he would direct you so that you had a hypothesis that would be more important and could be validated. His criticism was terribly important in your development of the science of investigative medicine. He was also my most important mentor in writing a scientific paper. A few years ago there was a Festschrift for Jack [S.] Remington, and one of his fellows published a reminiscence and showed the manuscript page as corrected by Jack where no line did not have some cross-out, comment, or addition. That’s what Jack had learned from Max, because Max would point out how the sense was off, or your subject was buried someplace in the middle of the sentence. The verb was hanging out somewhere not understood by the reader. Max was an important person, not only in developing a scientific framework, but he enabled you to write it up. Max’s thesis was that if you didn’t write it, you didn’t do it, and after a while you recognized how important that is. If you do something, you want to present it to the scientific community; you don’t keep it to yourself. You have to present it in a peer-reviewed manner so that it would advance that area of science. Now, Max was at the hospital until about 1983, and then he went to a nursing home, spent a few years there, and died in 1987. But there are none of us, none of the 112 fellows, who didn’t feel that his professional career was dominated by his experience as a Finland fellow. DR. SHULMAN: Can you speak to the issue of the pediatric component of those 112

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fellows? I’m also interested in Max’s interest in the pediatric as well as the adult aspects of the field of infectious diseases. DR. KLEIN: Max had very few pediatricians. In fact, the only 2 who were clinically oriented as well as research oriented -- the first two were Jim [James D.] Cherry and me. We, for the most part, were part of the Harvard medical service, and we saw mostly adult patients in consultations. But Sydney Gellis stimulated others to have some consultations sent our way, although Sydney was brighter than we were, and he certainly was more than capable of taking care of the problems. But he allowed us to participate in the program. There was no organized pediatric infectious disease. One of Sydney’s faculty was Charles [V.] Pryles, who had an interest in urinary tract infections, but there were these scattered folks. Even as you go back to medical school with Dorothy Horstmann, they didn’t come on consultations to the wards, and this would go through, I think, the early 1960s. As you recognized names of pediatricians who were important in infectious disease during that period, like Saul Krugman at NYU [New York University], Hattie Alexander at Columbia, Horace Hodes at Hopkins and Lou Wannamaker and Bob Good in Minnesota, they were individual investigators. They didn’t necessarily have services with fellows and provide complete research teaching consultations. That was to come in the 1960s. In 1966, Sydney had gone on to be dean of the Boston University School of Medicine, and then on to Tufts University School of Medicine, and Horace [M.] Gezon came to the City Hospital as director of pediatrics. Horace had had an interesting career in infectious diseases at the University of Pittsburgh School of Public Health, but he was a pediatrician, and he was a very good person, a very humane individual. But the areas of his investigations were often ones that weren’t attractive to me. He published a number of papers on staphylococcal colonization where he would take cultures from multiple sites, in the groin, around the umbilicus and the shoulders, and show that these were areas of high density of staphylococcal colonization of the newborn. And I felt there wasn’t the direct connection with disease that I had thought was important. But Horace certainly had made some contributions to that area of pediatric infectious diseases. But again, a single individual. It wasn’t a service. My role was to be the pediatrician of infectious diseases from the medical service relating to Horace. But he fostered my increased involvement, and I was an attending on the service a couple months a year. I liked Horace very much. Unfortunately, he had some medical issues that required him to resign in the early 1970s. But at that time, it still was a matter of the medical service being in charge of consultations throughout the hospital, including pediatrics. What would happen was that the adult fellows who saw pediatric patients would meet with me each day and review the management. For the most part, they were bright guys, and they were able to take care of almost everything outside of the newborn period. The newborn period was treacherous territory for an adult physician. They were shaken by the thought of going up to a premie and touching with even a gloved hand, let alone trying to figure out why this baby’s white count plummeted to a few thousand. DR. SHULMAN: Or even looking at a chest X-ray of a baby. [Laughter]

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DR. KLEIN: Yes, it was too small to really get it. And they have their adult stethoscope that filled most of the chest of some of their patients. But outside of newborns, the adult medical fellows, the ID [infectious disease] fellows, could take care of pneumonias, osteomyelitis, meningitis. It was pretty much the same as their experience in adult medicine had been. But newborns were certainly out of their area of comfort. This was still under the aegis of Max, and when Max decided not to do any further clinical work, Ed [Edward H.] Kass became the director of the infectious disease program. Ed was a dynamo. Ed was a genius. I think there are a handful of geniuses that I’ve met in my medical career, but Ed was one. He had an ability to bring people together. So as you look at the history of the Infectious Diseases Society of America, Ed is there. As you look to the purchase of the Journal of Infectious Diseases by the Infectious Diseases Society of America, Ed is there. As you look to the start of what is now Clinical Infectious Diseases (in 1980 it started out as Reviews of Infectious Diseases), Ed is there. Ed started an international infectious disease program [International Congress on Infectious Diseases]. They would meet in developing countries, like Cairo and Rio de Janeiro, not at some of the big infectious disease programs. Ed was a genius at organization, and he also was a very skilled investigator, and I learned a lot from him. He wanted me to take over the pediatric part. After a period of time, we started organizing a pediatric infectious disease program in the 1970s, with fellows, and that evolved to add more fellows and a structure with faculty. But I think there were very few such programs in the 1960s. I think it really starts in the late 1960s, perhaps, early 1970s, when there is a structure for pediatric infectious disease fellowships, programs of consultation, teaching, and even some pediatric programs being presented at the Infectious Diseases Society of America meeting. It evolved, so that I think in the 1970s most academic centers began to have at least one infectious diseases pediatrician, and, perhaps, the development of programs with training fellows and a young faculty that were able to be the triple threat in academic medicine: being independent investigators capable of getting grants, clinicians, as well as teachers. DR. SHULMAN: I think Minneapolis is probably one of the first places that had a fellowship program under the direction of the folks you mentioned, and, by extension from that, at the University of Florida, when Dr. Elia [M.] Ayoub moved from Minneapolis to Florida. DR. KLEIN: That’s right. We’d have to look to Ed [Edward L.] Kaplan and Paul Quie and the others who stayed in Minneapolis, and how that program developed. But Lou Wannamaker, who died too young, was certainly a part of that program in the 1960s, and how much we owe to them in terms of the Red Lake [Indian Reservation] studies and the other group A streptococcal programs and Paul’s work with insights into the immunology of infants and young children. DR. SHULMAN: Are there any other early career milestones that you’d like to talk about for yourself? You obviously touched on a bunch. DR. KLEIN: There were a number of facets in Boston that were not unique, but I

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think the collegial relationships among the hospitals and the colleges allowed for not only the development of skills, but also good research programs. So over time my group had relationships with Massachusetts General Hospital, Massachusetts Institute of Technology, and Mass Eye and Ear [Massachusetts Eye and Ear Infirmary], as we developed programs to study otitis media; with the Children’s Hospital Boston, in terms of the ENT [ear, nose and throat] program there and the skills they had that they could bring in audiology as well as in surgery. The undergraduate school at Boston University, where we became involved with leaders in speech and language, particularly a woman named Dr. Paula Menyuk, who taught me a lot about babble. Babble is the language of the young infant, and she was able to interpret babble. As we did our language and hearing studies of infants with a lot of otitis media, we looked at Paula to tell us whether the outcomes were good or bad and whether the child was really going to go on to have a language problem. We published a lot of papers together. Because of the resources of Boston, we were able to touch base with colleges, with the various hospitals, and I must say that if you could interest them in what you were interested in, then it was an easy relationship. There was no competitiveness other than a feeling of mutual insight into the type of program that you wanted to develop. There were a couple of other elements that evolved that were very gratifying to me, and one was getting residents invested in investigations. For example, in the early 1970s, Boston City Hospital, as a community hospital, always had a lot of questions about the febrile child. I got about a half a dozen of our house officers to do studies with me to look at risk features for kids who had invasive bacterial disease. It turned out there were a substantial number of febrile infants who had positive blood cultures, mostly for pneumococcus, some for Haemophilus influenzae type b, and occasionally meningococcus. We wrote a number of papers together with residents about the biology of the disease. In some cases blood cultures had been taken, the children not treated, and then subsequent blood cultures were negative, and the kids were well. So there was a phenomenon where one could have a pneumococcal bacteremia that was self-resolving without antibiotics, and that was an interesting phenomenon. I remember mentioning it to Dr. Finland, and he said, “Of course” [laughter], which he often said to something that I thought was astounding. But we learned a lot from that experience about the biology of the disease, and I got to be more aggressive about treating children who had risk features for invasive disease. Later on it was tempered by not only the introduction of a pneumococcal vaccine but also by the fact that a lot of these kids were resolving spontaneously and probably didn’t need antibiotics. But the studies of the febrile child were enlightening, and they’ll be a part of pediatric practice throughout our lifetime and for the indeterminate future, because there are always going to be kids with febrile illnesses. We may not resolve all the invasive disease by vaccines, and they’ll still be challenged by the few among the many who have substantial temperature elevations. I think the relationships with other hospitals and colleges was very gratifying. Developing investigative programs for the residents to participate in was very helpful. I think a number of them became fellows in infectious disease, and I felt that we had had a part in recruiting good young people into the field.

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It was also a golden time for getting a grant from the National Institutes of Health. The threshold for approval was not as intimidating as it is now. I always learned from Ed Kass that you didn’t lose by losing in grantsmanship, because you would throw 30 out, you kept throwing grants out, and if 3 came in you were in business. So you lost 27 times out of 30. Now, if you play baseball you wouldn’t make single A, but in medicine you could do it. Now, with our current technology, you could write grants, put them in a drawer, later edit them, resubmit, and perhaps have a better chance. In the bad old days, all of this was typewriter-driven [laughter] with Wite-Out®, and it wasn’t as easy to resubmit materials. But you still got grants. I always felt that you had to imbue in young people who were intimidated by the grant process that if you persevered you could make it, and that you had to continually challenge yourself to refine the ideas, to look at the reviews, to see where your reviewers had critiques that could be of value as you resubmitted the grant. But it’s a hard sell. Young people now are concerned that they will not succeed in this environment, investigative medicine, and I feel that somehow, through federal funding or private funding, young people in investigative medicine have to be nurtured so that we will have a future of productive research in pediatrics. DR. SHULMAN: You became very involved with the American Academy of Pediatrics Red Book Committee [Committee on Infectious Diseases] in 1973, and perhaps other areas of involvement, as well. Please tell us how you influenced the Red Book Committee and how that influenced you? DR. KLEIN: Well, there are so many areas in medicine where people open doors for you and are supportive. And Sam [Samuel L.] Katz nominated me for the Red Book Committee, and I am grateful to him for that opportunity. The Red Book Committee was an education, as new challenges were brought to the committee and they deliberated about what was best in management of infectious disease in infants and children. I was on the Committee for 2 terms -- I think it was 6 years -- but toward the end of that I was asked to be editor of the edition that was to be published in 1982. What I learned from that experience was how every word counted. Since others would adopt and follow your recommendations to the letter, you had to be sure that each recommendation was evidence-based, was solid. Many of them could not be evidence-based; there just wasn’t that kind of substance behind it. The other important aspect of editing was to avoid certain words, [laughter] like “should.” Should is an imperative. If you say, “You should provide X for a child who has Y,” the lawyers will hang on that and say, “You didn’t provide X for the child who had Y.” Now, you may have provided excellent management for that child, but “should” is an imperative that should be avoided at all costs. You learn a lot by an experience where your text will be a guideline to care. Now, the Red Book preface is very careful to say it’s only a guideline, but, in fact, it’s taken as a bible by most caretakers for children. But it was a wonderful experience that I shared with Phil [Philip A.] Brunell, Jim Cherry, Vince [Vincent A.] Fulginiti and others on the committee at the time, all of whom contributed substantially, including many outsiders from CDC. There are areas such as parasitology where we needed help, and they provided it. DR. SHULMAN: So your career has been long and extraordinarily productive, in terms of

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textbooks, an extremely impressive number of peer-reviewed papers, about 450. Speak to us, additionally, about how your career evolved, what you’re most proud of. DR. KLEIN: From an investigative standpoint, I’m most proud that I stayed at one hospital for my entire professional career, at least after the internship in Minnesota and the EIS experience. I had the support to stay at Boston City Hospital, that then was privatized as Boston Medical Center, and to see this community evolve and benefit from the extraordinary advances that were made during my professional career. Now, I start as a medical student in the 1950s, and there’s still polio, and classmates would come back from a summer having a paralyzed limb. It was terrible. It was a terrible disease that frightened parents, that had made them adjust their children’s summer so they couldn’t be in crowds, go to the movies. Then in 1955 we have this extraordinary presentation on the tenth anniversary of the death of [President] Franklin [D.] Roosevelt that the Salk vaccine worked. Then we have that story that follows that’s equally compelling about the failure to completely formalinize the vaccine so that there were cases of paralytic disease occurring in the limbs where the incomplete formalinization process allowed for live virus to be injected. Again, Alex Langmuir was an important player in deciding what to do when the first cases occurred in Idaho, and then there were cases in California. DR. SHULMAN: The Cutter incident. DR. KLEIN: The Cutter event and the first cases were in Pocatello, Idaho. To stop the vaccine program at a time when the public was so thrilled with the potential for preventing polio was tough. It took courage to make decisions to not only identify why it happened but also to immediately halt production, and to go back to basics and find out. It turned out that there was an extrapolation and a curve that Salk had used that was to lead to complete eradication of live virus, but it was a theoretical curve. They had to go back to the drawing board. But that experience of having a vaccine that prevented that terrible disease was so striking. But as we go to the diseases that really bothered us, such as meningitis due to haemophilus, what scared me most when I was working in the emergency room was the child who would come in drooling, aphonic, in whom you didn’t even dare look at the epiglottis because you were afraid that he would swallow his cherry swollen epiglottis. He was sent to the operating room immediately for placement of a tube, and it was all due to Haemophilus influenzae type b. Now there are a couple of minor players, but H. flu type b was it. And now we don’t see that. Young people, if you tell them about epiglottitis, it’s like malaria, but we see more malaria now, of course. [Laughter] And then you get the meningococcal vaccines, and the pneumococcal vaccine. I must say, one of the most thrilling moments in my professional career was serving on the Data Safety Monitoring Board of the clinical trial of Prevnar® 7. It was being performed in northern California by Henry Shinefield and Steve [Steven] Black, and I was on the committee that at times included Joel [I.] Ward, Jim Cherry, and Donna [M.] Ambrosino, among others. They enrolled 38,000 children, and it was randomized, blinded. Kids got either the PCV7 or a meningococcal vaccine. This is the 7 valent conjugate pneumococcal

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vaccine in the late 1990s. Bill [William C.] Blackwelder was the statistician. And we talked about what number of cases we should take a first look. We said 17 would be OK, because if, as example, there were 10 cases in the vaccine group and 7 in the controls, you’d stop the study, because there wouldn’t be any chance of a preference for the vaccine. If it was 11 to 6 in benefit of the vaccine, you’d probably want to continue it. If it was 14 to 3, you might stop it and say the vaccine worked. So on an August day, I get a printout. There were 4 patient groups, it’s A, B, C, D. In group A there were 12 cases of invasive pneumococcal disease. In group B there were 5 cases of invasive disease. In group C there are none. In group D there are none. But we still didn’t know which groups were the controls and which were the immunized. Within an hour we got a fax that A and B are the controls, and C and D are the immunized. And in this experience of 17 cases, they all were in the controls. There were none in the immunized. DR. SHULMAN: This is August of what year? DR. KLEIN: Must have been about 1998 because the vaccine was introduced in 2000. Well, that’s a eureka moment. You know, it’s one of those things where this huge effort to enroll 38,000 children, to follow them closely, all boils down to 2 sheets of paper, and all of a sudden you know that there’s something that is going to change pediatrics forever. This burden of pneumococcal pneumonia, meningitis will be diminished substantially. That was thrilling. I think being in investigative medicine permits those eureka moments that give meaning to what we do. DR. SHULMAN: Please tell us more about breaking the code, when you learned that it was 17 to zero in terms of invasive infections in the vaccine and control groups. DR. KLEIN: The efficacy of the vaccine was thrilling. And at the time the 3 of us who were on the Data Safety Monitoring Board, Bill Blackwelder, Donna Ambrosino, and I, were on a conference call. Blackwelder was in Moscow, so we had to adjust the time for him. [Laughter] But it was a eureka moment, and I knew that it was going to change a lot of our framework for dealing with serious infectious diseases in children. I wrote a commentary for Pediatric Infectious Disease Journal, which I think was called “The pneumococcal conjugate vaccine arrives: a big win for kids,” [2000 Mar; 19(3):181-2] and it was. It meant that hopefully the vaccine would be available for every child. Of course, the cost has limited access in many developing regions, but I think it followed a thesis that I feel very strongly about: that no child should suffer a vaccine preventable disease, with the efforts of the NGOs, the governments, the WHO [World Health Organization]. These things we can do. We may not be able to stop, you know, internal strife, but we ought to be able to deliver vaccines and build enough wells for them to have potable water. I think the theme of our colleagues in infectious diseases is and will be, as we look to vaccines for HIV [human immunodeficiency virus], for malaria, tuberculosis, that as they become available no child should suffer from a vaccine-preventable disease. DR. SHULMAN: What other advances during your career, Jerry, do you feel have affected children and the field of pediatric infectious diseases, and general pediatrics, the most?

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DR. KLEIN: Well, what’s interesting to me is the public perceptions that we have to deal with, and that I don’t think we’re dealing with entirely successfully, that a parent today should feel that there are reasons why their child should not be immunized, because of some crazy who said something about the child developing autism or some other adverse event. The vaccines that are available now have been so thoroughly tested, have had so much clinical use, that there is no reason for a child not to be completely immunized with the available products. Now, there’s a degree of risk that I think the public, as it regards vaccines, is unable to deal with, and that is that with everything you do in life, there’s a risk. If you go up in the elevator to your hotel room, the elevator may malfunction. It may stop. You walk across the street, there’s a risk. But in terms of vaccines, the public almost demands complete absence of risk, and that’s unavailable in any drug, any food product, or any vaccine. Somehow, we have not succeeded in presenting that framework for understanding that there may be rare events associated with vaccines. We’ve been very fortunate in saving ourselves and the vaccine industry and children with the development of the [National] Vaccine Injury Compensation Program. A miraculous but hardworking group of members of the American Academy of Pediatrics and parent advocate groups proposed legislation that was passed in 1986 that essentially made it a no-fault insurance program for those who administer vaccines, as well as for the manufacturers of approved vaccines. So this was an extraordinary, important public policy that said there may be risk. There may be some children who will suffer from an approved vaccine that provides much more benefit for the public good than for a misadventure. And it avoided the tort system. It is a special master, who determines whether there is a possibility of an adverse event associated with the vaccine. There’s an expert for the plaintiff and an expert for the government, and the special master, who has a legal background, not a scientific background, provides a judgment about compensation for that plaintiff. In many cases where the evidence favors the vaccine, the special master may still approve a payment to the plaintiff, and often I think some of us in the medical community would feel it was inappropriate. But it doesn’t matter, because it’s provided a safety net that allows for compensation through this special mechanism instead of through litigation that I think has, in the end, been a major advance. I’m not sure how widely it’s available in other countries, as well. But this is a 75 cent tax on every vaccine dose. So if you have MMR [measles, mumps, rubella] vaccine then that’s 3 times 75 cents. It was a couple billion dollars in the pool, and a couple billion dollars that have been provided over the years since 1986 to plaintiffs. It’s been liberally provided to plaintiffs. There is always a threat to the moneys that are available if an association to something like autism were to be found by the special masters. The funds would be wiped out. So we have to be very careful that the science is presented as best it can be, and that frivolous suits are not permitted to go forward. But certainly the Vaccine Injury Compensation Program, administered by Geoff [Geoffrey] Evans and others, has been an important part of the vaccine story in the past 30 years. DR. SHULMAN: Jerry, how do you view the full spectrum of possibilities with respect to research support that’s been available to you in your career, and how that compares to what is available to young investigators today? DR. KLEIN: If we go back to the period when I was a fellow, with Max Finland, we were studying the new penicillins: the pharmacokinetics, the in vitro activity studies, the

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clinical efficacy trials. They were all supported by industry. NIH would not be interested in supporting that. Nonprofits would not be supporting. But Max was an indisputably honorable individual, completely ethical and honest, and nobody would challenge that his paper on in vitro activity of oxacillin or methicillin was industry supported and therefore compromised. Unfortunately, over the years industry support has become tainted, some in a manner that is appropriate where the industry may control both the trial and the presentation of data. But it’s been, I think, overstated in that if you have a new product, a new antibiotic, it’s unlikely that the NIH is going to support the necessary studies to bring that product to clinical use. So who is going to support it? It’s going to be industry. Now, the fact that the industry supports it doesn’t mean that it’s compromised by their input. The investigator has to be very critical and scrupulous in making sure that the studies are done and are tight in terms of controls and randomization, blindedness, but it can be done well, and should be done well. I’m concerned that our young residents, when they hear data presented about a product and that it was supported by a company, immediately denigrate it. I think that is an unfortunate transition to cynicism that we have an obligation to respond to. At my institution, and I guess many institutions, reps [pharmaceutical representatives] used to have pizza for lunch, have pens with the name of the product on it, support continuing medical education [CME] programs. Those all now are denied by the institutions. I find that the companies were often a source of important educational provisions, sometimes in supporting the CME efforts that were non-product oriented, but also in providing information. If you wanted to know about the interaction of their drug A with another drug B, which information isn’t available to you, even now with Google, but it was available in the archives of the industry, and the rep could find it for you. So we lost an opportunity for education, and for obtaining information about product. I think we’ve extended that concern for industry oversight and influence to a degree that is unnecessary, and I would hope that could be righted over time. But right now I’ve been in grand rounds where some data were presented and a house officer would say, “Well, how could you trust that data if the study was supported by industry?” It’s like they don’t understand the reality of development of product and the necessary steps for such a product. So I think there’s an equilibrium that can be achieved where industry and academia can coexist in a productive environment that permits appropriate funding for educational programs as well as research, to the benefit of the students, the investigators, and the companies. I’m afraid we’re not there, that we are now in a very negative period where anything that is industry supported is felt to be compromised. It’s not true, but it delays product development and also the educational advantages that we had from industry support. My mentor, Max Finland, was very democratic, and very unbiased. He took money from everybody, so he had no prejudice. He wasn’t beholden to any one company. But if there was a product that he felt was of potential value, he would study it, and he had a reputation for honesty that permitted funding by the companies. And I think that’s the way it should be done today. DR. SHULMAN: This topic sort of segues into the next topic, which is how do you see that medical education has changed over time?

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DR. KLEIN: It’s an extraordinary change. I still use textbooks. Many of my students have only an iPad® or an iPod®, and have Up To Date or the Red Book or others on their handheld instruments. Some of the textbooks are available by eBook, as well. It’s certainly a different framework for getting information about your patients than in the past. But it’s going to continue. Those who write the textbooks in the future will be looking to have a product and see how the information can be best presented in this new technology. Publishers may publish some print versions of textbooks, but a lot of it will be bundled with several textbooks being available through libraries, and then to your handheld library. In terms of the education of the house staff, I’m concerned that the Libby Zion [Law] experience has resulted in residents having limited experience with the continuity of disease. For example, if you have a child that comes at midnight with diabetic ketoacidosis, and you begin to adjust the fluids, and provide the insulin, and you see the early signs of resolution, and it’s now 6:50 in the morning, at 7 o’clock you have to go home. It’s not permissive; you’re obligated to go home. So your experience in that important patient, that important learning experience with diabetic ketoacidosis, is aborted. I don’t think that’s an advance in education. They’ll be a little better rested when they come back late that night and see that the child is all well, but having missed the interval steps to me means they’ve lost that important experience. Second, there has to be a middle ground where continuity in the care of the patient is permitted. I don’t think it’s good for the patient, either. The handoff, where the resident at 7:00 a.m. has to relate this complex series of events to somebody coming on, and that person has to absorb all that information so they can properly continue the plan, means that the patient may be vulnerable during that time. Then at 3 o’clock, when that resident, who’s been on since 7:00 a.m., has to go to his clinic, and, again, has to hand off to the next individual, that can have a potential loss of information. I think the response to house officer hours has been overdone, and that we may have more rested but less informed house staff. When I was an intern and I’d started in a weekend rotation on Saturday morning and come home Monday night, that was a lot. It probably would have benefited from some restriction in hours, but not to the point where you lose the value of your relationship with the patient, and you lose the educational experience. I think at some point the powers that be will recognize that and make some adjustments, but right now it’s a very rigid system that demands that the relationship with the patient and the educational experience be terminated earlier than it should. DR. SHULMAN: I can’t agree with you more. Jerry, where do you see pediatrics and the pediatric infectious disease field going in, say, the next 10 years? DR. KLEIN: I think it’ll be a very exciting decade. I think we will see vaccines, perhaps, for the big 3: malaria, HIV, and tuberculosis. There will be global transmission of microbes, so that something that will start off in Central Africa, as HIV did, will, again, emerge as a world threat. The transmission of organisms by the various easy modes of transport, such as SARS or the Asian flu that began in Hong Kong and rode on airplanes to Toronto and other sites, will continue. So we’ll have to be alert to global epidemiology. I think there will be excitement for young people in the field as they venture into global medicine, but I also hope that they won’t forget the local problems. I may have mentioned

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that in Boston many of our bright young residents want to have an international experience, and often find their way to developing regions. I try to convince them that there’s developing regions in our backyard, and that there are problems of poverty, of violence, social issues, homelessness that impact on disease in our community, and that they don’t have to go to Zimbabwe to be challenged by the issues in Roxbury. DR. SHULMAN: How about looking even farther afield? Fifty year timeline? (Laughter) Will we all be chips? Genomic medicine influence? What do you think? DR. KLEIN: Well, I think in the decades ahead there will be more universality of products, of disease, of rapid transmission of organisms. Genetics is undoubtedly going to play a part in identifying risk features, as well as optimal modes of management. I think it will be exciting. I think young people who today are in training will have a wonderful experience in medicine, and that there will be more than enough to excite them in the field that we found so gratifying, infectious diseases of infants and children. It’s unlikely that we’re not going to have new organisms that will challenge us, and we have only the HIV experience, the Ebola virus, Hong Kong Asian flu, to give us some insight as to how disease can spread rapidly, can be fatal, and that we’ll need to have our fingers on the pulse of global epidemiology to be ahead of the transmission of those new organisms into our communities. DR. SHULMAN: Do you believe that physicians just now entering medical school can look forward to a career that’s as fulfilling, as exciting as that which you’ve experienced since you entered medical school? DR. KLEIN: I think it’ll be very exciting, but it will probably be qualitatively different. It may be that we’re going to have a mode of surveillance of infants that’ll be much more precise in terms of risk features and pathogenesis than we have now. There are certainly enough gaps. I’ve followed the field of otitis media for decades, and there are still important core issues that are unanswered. We don’t know why some children have recurrent episodes, and severe episodes of otitis. It doesn’t appear to have a known immunologic basis, perhaps an anatomic basis, a genetic basis. The pneumococcal conjugate vaccine is not as effective for prevention of recurrences of otitis as it is for prevention of invasive disease. We don’t know the immunology of the middle ear to answer some of those questions. So I think even without going into exotic fields, that we’re still at a point where there are a lot of issues about early identification of disease, optimal management of those diseases by insight into their pathogenesis, that leaves a lot of work to be done for the future generation of physicians. I think pediatric infectious disease will be, as it has been, one of the most exciting areas for young people to be engaged in. DR. SHULMAN: Well put. Jerry, are there any other accomplishments in your career that you haven’t yet touched on that you’d like to discuss? DR. KLEIN: The area that I’ve been interested in the last few years through participating in a study of neonatal sepsis in Pakistan and Bangladesh is how we transmit some of the management accomplishments to areas in regions that are still developing. A

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child born in Bangladesh should have an opportunity for a quality of life that is comparable for a child in the developed regions. We’re a long way from that. But more money is contributed by government and nongovernmental agencies, such as the Gates Foundation, and the results are implemented by WHO and local health programs, to reduce the burden of disease from infants and children. It will take generations before you can have an infant born in a region of the world who will be able to have a quality of life that will be comparable to those in developed regions. The study that I’m involved in, looking at simplified antibiotic regimens for infants with suspected sepsis, gets the child over one hurdle, but then they have multiple hurdles of poverty that entrap them for the rest of their lives, and don’t permit them to break out, and to become educated, contributing citizens to their community. You mentioned 50 years ahead. Well, I think these problems for billions of people will be a 50-year project. DR. SHULMAN: Thank you very much, Jerry. This has been a most informative discussion, and I appreciate your candor and willingness to meet. Are there any other comments you’d like to make, please? DR. KLEIN: Well, I certainly appreciate the opportunity for this oral history, and to be able to relate some of the experiences that I’ve had. Medicine has been a gratifying experience for me. I’ve loved it. I’ve loved being a doctor. I’ve taken pride in being able to take care of patients, to teach young students, to try to imbue them with some of the important issues that I think will enhance their career, and to see them develop, and to see a student whom you have nurtured take full flight and be an independent investigator. I think it’s been a privilege to be in a setting where you could be creative, have an idea, execute that idea, see it in practice, to have the social relationships with your colleagues, and with students. And I must say that particularly pediatricians, because they take care of vulnerable infants, are nice people, and pediatric infectious disease people are the best. So much of the gratification in my medical experience has been the close relationships I’ve had with colleagues. DR. SHULMAN: Jerry, thank you so much for all your contributions, and for participating in this discussion. Thanks again.

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Index

A 

Albrecht, Robert M., 10 Alexander, Hattie, 14 Ambrosino, Donna M., 18, 19 American Academy of Pediatrics, 17, 20 Ayoub, Elia M., 15 American Academy of Pediatrics Committee on

Infectious Diseases, 17 

B 

Bellevue Hospital, 2 Black, Steven, 18 Blackwelder, William C., 19 Boston City Hospital, 11, 14, 16, 18 Broadway Melody, 3 Bronx High School of Science, 1 Bronx, New York, 1, 2 Brunell, Philip A., 17 

C 

Castle, William B., 12 Cherry, James D., 14, 17, 18 Cooke, Robert E., 5 Cutter event, 18 

D 

Dennehy, Brian, 4 Dowling, Harry F., 11 

E 

Epidemic Intelligence Service, 3, 9 Evans, Geoffrey, 20 

F 

Finland, Maxwell, 4, 11, 12, 13, 14, 15, 16, 20, 21 Forbes, Thomas R., 4 Fulginiti, Vincent A., 17 

G 

Gellis, Sydney S., 11, 14 Gezon, Horace M., 14 Good, Robert A., 6, 8, 9, 11, 14 Green, Morris, 5 Greenberg, Daniel, 2 Greenberg, Morris, 2, 3 

H 

Haemophilus influenzae type b, 16, 18 Henderson, Donald A., 9 Hodes, Horace, 14 Hoffman, Philip Seymour, 3 Horstmann, Dorothy M., 6, 14 

I 

Infectious Diseases Society of America, 15 

K 

Kass, Edward H., 15, 17 Katz, Samuel L., 17 Keefer, Chester S., 12 Klein, Linda, 7, 10, 11 Krugman, Saul, 14 

L 

Langmuir, Alexander D., 9, 10, 18 Lerner, A. Martin, 11, 13 Libby Zion Law, 22 

M 

McGowan, John E. Jr., 11 Melnick, Joseph L., 6 Menyuk, Paula, 16 Minot, George R., 12 

N 

National Vaccine Injury Compensation Program, 20 New York State Department of Health, 10 Nyhan, William L., 6 

P 

Paul, John Rodman, 6 penicillin, 12 Plotkin, Stanley, 1, 10 Prevnar® 7, 18 Pryles, Charles V., 14 

Q 

Quie, Paul G., 11, 15 

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R 

Red Book: Report of the Committee on Infectious Diseases, 17, 22 

Remington, Jack S., 13 

S 

Salk vaccine, 18 Schiebler, Gerold L., 11 Senn, Milton J. E., 5 Shinefield, Henry, 18 smallpox, 2 Summerland, William, 8 

T 

Thorndike Memorial Laboratory, 12 

U 

Union College (Schenectady, New York), 1, 3 US Centers for Disease Control, 3, 9, 17 US Epidemic Intelligence Service, 3, 9, 10, 18 US National Institutes of Health, 17, 21 

V 

Veterans Administration Hospital, West Haven, Connecticut, 5 

W 

Wannamaker, Lewis W., 5, 6, 11, 14, 15 Ward, Joel I., 18 

Y 

Yale School of Medicine, 4, 5, 6 

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56