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Biography: Walter T. Hughes, MD: Pioneer and leader in the battle against pneumocystis carinii pneumonia
Biography Walter T. Hughes, MD: Pioneer and Leader in the Battle Against Pneumocystis carinii Pneumonia B. Lee Ligon, PhD With the increased prevalence of human immunodeficiency virus and acquired immunodeficiency syndrome in children and adolescents, diagnosis and treatment of other associated diseases, many of which pose specific risks for this particularly vulnerable population, are of concern to pediatricians. An important opportunistic infection associated with this increased prevalence is Pneumocystis carinii pneumonia, which recently has occurred in epidemic proportions in these populations. Untreated, the disease always is fatal. Since his first descriptive report on P carinii pneumonia in 1971, Walter T. Hughes, MD, has been the unequaled authority on the disease, its prevention, and its treatment. He is the subject of this article, which seeks to honor his outstanding research accomplishments, his commitment to his profession and to his patients, and his devotion to his family, all of which find their source in his faith. Copyright © 2001 by W.B. Saunders Company
ith the increased prevalence of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) in children and adolescents, as well as in adults, specialists in infectious diseases have encountered numerous challenges in the diagnosis and treatment of other associated diseases, many of which pose specific risks for this particularly vulnerable population. An important opportunistic infection associated with this increased prevalence is Pneumocystis carinii pneumonia (PCP), which earlier took the lives of patients who had been cured of leukemia1 and more recently has occurred in epidemic proportions among patients with HIV and AIDS. Untreated, the disease always is fatal.1 Since his first descriptive report on PCP in 1971, Walter T. Hughes, MD, (Fig 1) has been the unequaled authority on the disease, its prevention, and its treatment. Having devoted his entire career to the battle against a disease that poses particular dangers to the immunocompromised patient, he has emerged victor, having developed both prophylactic and treatment regimens. The victories once gained for patients with leukemia, cancer, and other such diseases are now being applied to the newest population of severely vulnerable patients, those with acquired immunodeficiencies. The recipient of the Pediatric Infectious Diseases Society’s 1997 Distinguished Physician
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From the Department of Pediatrics, Baylor College of Medicine, Houston, TX. Address correspondence to B. Lee Ligon, PhD, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin, MC 3-1000, Houston, TX 77023. E-mail: [email protected] Copyright © 2001 by W.B. Saunders Company 1045-1870/01/1204-0010$35.00/0 doi:10.1053/spid.2001.28615
Award (Fig 2), Dr Hughes is the subject of this article, which seeks to honor his outstanding research accomplishments, his commitment to his profession and to his patients, and his devotion to his family, all of which find their source in his faith.
Early Childhood and Education Walter Hughes (Fig 3) was born in 1930 on a farm in southeast Tennessee to Walter and Millie Hughes. Because Cleveland, TN, was the nearest town, it was given as his place of birth, but the actual location was the family farm. Walter Hughes, Sr, inherited a lumber company from his father and grandfather, and despite having little formal education, he was able to develop the company while also farming on the side. Today, Dr Hughes remembers his father as “a remarkably honest, highly intelligent, jovial, and lovable man” (Dr Walter Hughes, personal communication, July 22, 2001 and August 3, 2001). Unfortunately, when young Walter was only 9 years old, his father died of pneumococcal pneumonia, leaving his wife to rear Walter and his 2 younger siblings. She managed remarkably well. She gave the 3 children religious and moral training at home and, without the aid of Pell grants, welfare aid, or financial scholarships, each one received a strong academic education. Dr Hughes’ brother Joe became an orthopedic surgeon in Atlanta; his sister Katherine became the wife of a prominent university professor, also in Atlanta; and as this article recounts, Dr Hughes became a renowned scientist. Her children all credit their devoted mother with providing them the resources and helping them develop the resolve needed to achieve academically (Dr Walter Hughes, personal communication, July 22,
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Figure 1. Dr Walter Hughes. (Courtesy of St. Jude Children’s Research Hospital.) 2001). She also instilled in them a strong basis for their Christian faith and appreciation for its principles (Dr Walter Hughes, personal communication, July 27, 2001).
Walter Hughes is a product of public education from kindergarten through medical school, for which he is grateful. His elementary school days date back to the time when schools were equipped with chalkboards, tablets, and no. 2 pencils. The school Walter Hughes attended also had a wind-up phonograph for classical music, which was played once a week, and it was noted for its dynamic, disciplined, and dedicated teachers. He considers this time an opportunity to learn about the real world and how to cope. During these early years, Walter encountered a distinct challenge to his education endeavors. He had a mild form of dyslexia, and his experience predated the recent recognition of the problem and the various approaches to accommodate students who have it. He discovered on his own how to deal with it by writing or rewriting everything he heard or read. The procedure is one he still uses for important topics (Dr Walter Hughes, personal communication, July 22, 2001). In high school, Walter’s interests leaned heavily toward music and other fine arts. He played the trumpet and the French horn in the band and in the orchestra, he sang in the chorus, he was president of the Thespian Society, and he had a lead in the senior play. All of his close childhood friends through high school entered various fields of music, theater, or business, but Walter Hughes chose to go another route. He notes that his decision not to pursue any of these interests as a career was fortunate because he “was never a very good musician or actor and definitely not inclined to business” (Dr Walter Hughes, personal communication, July 22, 2001 and August 1, 2001).
Medical Training and Military Service The choice of medicine for a career was not an easy one to make. He also considered the clergy, architecture, and
Figure 2. Dr Walter Hughes receiving the Distinguished Physician Award at the Annual Awards Ceremony of the Pediatric Infectious Diseases Society, 1997. (Courtesy of Dr Walter Hughes.)
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Figure 3. Walter Hughes at 3 years of age. (Courtesy of Dr Walter Hughes.)
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of cases of orophryngeal tularemia that he had studied. That paper was to change the course of his career. Although he had been considering a career in hematology, events would alter that plan and take him in another direction. While completing his training in pediatrics, Dr Hughes was drafted into the Army with an initial assignment to Korea (Fig 4). When authorities learned of Dr Hughes’ experience with tularemia, they decided instead to send him to Walter Reed Army Institute of Research Unit at Fort Detrick, MD, a highly classified research center for biological warfare, a Mecca for microbiologists. The question Dr Hughes kept asking himself was “why me?” Little time passed before he learned the reason. The Cold War was just beginning, and rumors that the Russians had learned to aerosolize Francisella tularensis, a prominent candidate for bacterial warfare that was under study for this purpose by many countries, created immense concern. Furthermore, the Department of Defense had learned that the Soviets had immunized thousands of their people against tularemia. The United States initiated a major effort for defense against tularemia at the facility in Fort Detrick, and 4 young officers (Drs Richard Hornick, Ken Vosti, Bill Burmeister, and Walter Hughes) were added to a team of senior investigators. They spent 2 years evaluating a vaccine in trials with monkeys and human volunteers. As a result of this experience, each of the 4 of them later pursued careers in infectious diseases and academic medicine (Dr Walter Hughes, personal communication, July 22, 2001 and August 1, 2001).2
Early Medical and Research Career journalism. His college aptitude tests ranked him very high in fine arts and language, but only average in science. Nonetheless, as he considered all these options, he was drawn to medicine primarily because it seemed to offer more opportunities to help people, a factor that played a strong role in the decision of a young man who had grown up with strong altruistic inclinations because of his religious background (Dr Walter Hughes, personal communication, June 22, 2001). In 1950, Dr Hughes was accepted at The University of Tennessee College of Medicine. Unlike some of his colleagues, Dr Hughes did not consider the experience fun, and he recalls it as a 3-year marathon to pass examinations. Among the demands of medical school was that he improve his skills in overcoming the dyslexia. For the primary texts, he wrote extensive abbreviations, many of which were duplicated for his classmates. He recalls that he “passed biochemistry by writing the endless structural formulas of organic compounds on rolls of toilet paper (it was free in the dorm).” Only after medical school did he become thrilled with the study of medicine (Dr Walter Hughes, personal communication, June 22, 2001). After receiving his medical degree and completing a year of rotating internships, Dr Hughes began a residency in pediatrics at the Le Bonheur Children’s Hospital in 1955. While there, he was encouraged by his chief and dedicated mentor, Dr James Ettledorf, to publish a paper on a series
After being discharged from the Army, Dr Hughes entered private practice in his hometown of Cleveland, TN. The
Figure 4. Dr Walter Hughes, Captain, US Army, 1957. (Courtesy of Dr Walter Hughes.)
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practice was very busy with wall-to-wall patients, requiring that Dr Hughes work from dawn to bedtime. This experience was invaluable to his subsequent years in academic medicine. He contends that nothing can better prepare the university professor in clinical pediatrics than a couple of years of private practice in a small town (Dr Walter Hughes, personal communication, August 1, 2001). His stay in Cleveland was short-lived. After 2 years, he left to engage in academic research in infectious diseases at the University of Louisville, where he developed an interest in what he considered “odd infections,” namely those caused by fungi. Primarily interested in the aflatoxins produced by Aspergillus species, Dr Hughes also became involved in research on the then emerging spectrum of invasive mycoses in children with cancer.2 During a remarkable tenure at Louisville, he proceeded from Instructor in 1961 to Professor in 1966. During this period, he received on 3 occasions the Most Outstanding Clinical Teacher Award, wrote a book entitled Pediatric Procedures, and established a research laboratory to study opportunistic fungi. In bedside teaching, he never allowed his students or residents to use the abbreviation LMD (local medical doctor) for the person who referred a patient. Instead, they were required to give the name of the local medical doctor. In 1968, he served as Acting Chairman of the Department and as Physician-in-chief of Children’s Hospital. The experience convinced him that his heart was in the research laboratory with infectious diseases rather than in departmental administration, and he stepped down from the post (Dr Walter Hughes, personal communication, August 1, 2001).2 A year later, he was called to a new hospital that was focusing on children with cancer and hematologic diseases.
St. Jude Children’s Research Hospital and Development of PCP Prophylaxis In 1969, Dr Hughes was invited by Donald Pinkel, MD (Fig 5), the visionary director of St. Jude Children’s Research Hospital, to join the new institution, which had been open only 7 years. Hughes is quoted as saying that: At other places I interviewed they took me to fancy restaurants. When Dr Pinkel picked me up at the airport, he brought me straight to St. Jude and we spent 3 hours or so going over the kind of research they were doing. Then, he drove me to his house for hot dogs and beer. At 2 AM, I got back to my hotel and he told me he’d pick me up at 7 AM so we could talk some more. By the end of that day, I was completely caught up in the philosophy of St. Jude.3
Even in its early years, the hospital was gaining a reputation for outstanding research. Under Dr Pinkel’s direction, a curative therapy for acute lymphocytic leukemia, until then a uniformly fatal malignancy, had been discovered. Dr Hughes accepted the invitation and joined the new faculty of clinical investigators and basic scientists who were focusing on catastrophic diseases of children. He was Chief of the Infectious Diseases Service, which comprised 1 person—Walter Hughes! As the sole staff member, Dr
Figure 5. Dr Donald Pinkel. (Courtesy of St. Jude Children’s Research Hospital.)
Hughes made rounds every day, saw patients every day, and was on call every day. His daily encounters with children showed him that their valiant battles against their diseases left them with no defense against infections.3 During the next 8 years, Dr Hughes expanded the Service, which soon grew to a Division, and then to a Department, and he was in the chairmanship role again. When Dr Hughes came to St. Jude, his particular focus of research was in mycology, specifically the potent carcinogenic aflatoxins of Aspergilus flavus.1,2 This work was interrupted by the occurrence of an emerging infection of great magnitude at St. Jude (Dr Walter Hughes, personal communication, August 1, 2001). Numerous cases of pneumonia caused by P carinii were occurring among an increasing population of cancer patients. He had never seen a case of PCP, but he was about to become quickly engulfed in its devastating consequences. By the early 1970s, they were seeing 30 to 40 cases a year, and Dr Hughes was being taught by patients, oncologists, and pathologists about the disease that was taking the lives of patients cured of leukemia. At the time, the only effective therapy for PCP was pentamidine isethionate, which had to be ordered from the Parasitic Disease Branch at the
Walter T. Hughes, MD Centers for Disease Control and Prevention (CDC) on a case-by-case basis. The drug, which had to be administered intramuscularly, had adverse reactions in 70 to 80 percent of patients.1 The obvious need for better therapeutic drugs led Dr Hughes to establish an animal model for PCP in his laboratory, following the method devised by Dr Jack Frenkel in Kansas City.4 They quickly and easily provoked PCP in rats by simply administering cortisone acetate. The pneumonitis, which occurred in 90 to 100 percent of the animals, was remarkably similar to that in humans. The first vaccine was used to immunize the rats, which attained high antibody titers. However, after the animals were challenged with cortisone acetate, all of them died. Dr Hughes later noted that the deaths were disappointing, but not necessarily surprising because they had already found high antibody titers in cancer patients who had developed PCP.1 After trying several other compounds, Dr Hughes and his team turned to a combination of trimethoprim and sulfamethoxazole (TMP-SMX)2 after learning that evidence existed indicating that the folate antagonist fansidar was effective in treating PCP in Iranian infants. Dr Hughes also had heard from his former chief, Alex Steigman, MD, of its use as an antibiotic in Europe. Because the combination was not marketed in the United States, Dr Hughes contacted 2 pharmaceutical companies and requested a small supply to test in the animal model. One of the companies responded by providing a limited amount, and St. Jude provided the rats. The study, which cost a total of approximately $300,1 showed striking therapeutic and prophylactic effects.5 Immediately, a pilot clinical trial in patients with mild PCP was undertaken, and the drug administered orally proved to be effective.6 A randomized clinical trial comparing oral TMP-SMX with intramuscular pentamidine in patients with PCP of any severity showed a therapeutic success rate of 75 percent for pentamidine and 77 percent for TMP-SMX; the latter also lacked significant adverse effects.1,7 These successes indicated that development of chemoprophylaxis for PCP was a reasonable possibility, and in 1974, Dr Hughes and his team began a double-blind, placebo-controlled randomized study in children with cancer at high risk for PCP, 80 in each group. Because halfway through the study the overall incidence of PCP had been reduced 50 percent, strongly suggesting success, Dr Hughes’ oncology colleagues began to pressure him to stop the study, break the code, and place all the patients on TMP-SMX. However, Dr Hughes had reservations about doing so. One concern was that the broad-spectrum antibiotic activity of TMP-SMX might result in the replacement of PCP with a concomitant increase in other infections such as candidiasis and Pseudomonas aeruginosa infections. Another concern was that the antifolate activity might diminish host folate stores when given along with drugs such as methotrexate. Unless these and other questions were addressed, he feared that physicians might be hesitant to institute TMP-SMX prophylaxis and further placebo-controlled studies for adverse effects could never be justified because
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of demonstrated efficacy for PCP prophylaxis1 (Dr Walter Hughes, personal communication, August 1, 2001). The controversy became so intense that the issue came under review and was put to a vote by the faculty, which was favorable for continuing the study until completion.1 The final results showed unequivocally the value of prophylaxis: 21 percent of the placebo group had PCP, whereas none of the treated group had PCP infection, nor was the microbial flora significantly affected. The drug was determined to be safe.8 Dr Hughes (Fig 6) noted later that the study also revealed another lesson often overlooked in evaluating the true side effects of drugs: adverse effects occurred with equal frequency in the control and treated groups and 2 patients who had been removed from the study because of severe rash and neutropenia later, when the code was broken, were found to have been part of the placebo group.1,9 Since that study, all patients with leukemia treated at St. Jude have been placed on TMP-SMX prophylaxis, with the result that no cases of PCP occurred during the next 5 years10 and only an occasional sporadic case occurred during the course of the next 20 years, despite an increase in the number of high-risk patients and more intensive chemotherapy for cancer1 (Dr Walter Hughes, personal communication, August 1, 2001).
Figure 6. Dr Walter Hughes in his laboratory at St. Jude Children’s Research Hospital in 1976. (Courtesy of St. Jude Children’s Research Hospital.)
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Johns Hopkins University School of Medicine and the Call to Address AIDS
Research for Alternative Medications for PCP
In 1977, Dr Hughes “was lured away from Memphis”3 to Baltimore, where he accepted the post of Director of the Division of Infectious Diseases in Pediatrics and Eudowood Professor of Pediatrics at Johns Hopkins University School of Medicine. Work on PCP continued, but at a low level, primarily because the importance of P carinii was not evident. An unusual event led to new research and, ultimately, to Hughes’ return to St. Jude. In 1981, he was speaking at Grand Rounds at the University of Pittsburgh. At the completion of his lecture, Dr Hughes was handed a note marked “urgent.” It was from Dr Jeffry Green at New York University Medical Center; Dr Green was asking for advice in treating a young man who was suffering from PCP and an unidentified underlying disease. Although TMP-SMX had been started and the patient had shown some improvement initially, an exfoliative rash and neutropenia had developed. Dr Hughes recommended that the medication be changed to pentamidine and requested that Dr Green let him know the outcome. Several weeks later, Dr Hughes received a letter from Dr Green, who provided a detailed report charting the patient’s course until recovery. Included in the correspondence was a comment that the patient was the fifth case of P carinii pneumonitis Dr Green had seen among young homosexuals at their institution and that every case had occurred within a short span of time. Dr Green suggested that perhaps the homosexual population had, as he put it, a “heretofore unrecognized acquired immunodeficiency.”1 The findings of Green and colleagues led to the publication of the classic paper, coauthored with Henry Masur, describing the first cases of AIDS from the east coast.11 In many ways, these cases of PCP were responsible for the identification of AIDS in the United States; they also account for the exaggerated rate of adverse effects that later were reported on TMP-SMX1 (Dr Walter Hughes, personal communication, August 1, 2001). The increased incidences of adverse reactions to TMPSMX experienced by patients with AIDS led to demands for more dosages of pentamidine, and the supply at the CDC soon was diminished. Much to the surprise and concern of the CDC staff, May and Baker, the manufacturers in England, had stopped making pentamidine and no other source was available anywhere in the world. Considering the limited supply of pentamidine and the adverse effects of TMP-SMX in patients with AIDS, Dr Hughes went back to work on an animal model to search for more drugs. His decision involved a return to St. Jude in 1981, and a major factor in leaving Baltimore was his family’s love of Memphis as a place to live. Dr Hughes holds Hopkins close and has continued to serve on the faculty as lecturer in pediatrics for the past 20 years (Dr Walter Hughes, personal communication, August 1, 2001).
On his return to St. Jude, Dr Hughes resumed the chairmanship of the Department of Infectious Diseases, a position he held until 1995. He recalled that “it was very reminiscent of 1969 because while I was gone everyone else left too. Here I was at St. Jude again with a faculty of 1.”3 He quickly set to work recruiting a new staff, 1 of whom was Dr Jerry Shenep, who always felt a sense of team spirit working alongside Dr Hughes.3 By 1984, Dr Hughes was able to report animal experiments showing that diamino-diphenyl sulfone (dapsone) had potent activity against P carinii and that the activity could be enhanced synergistically with TMP.12 Because he had no patients with PCP at St. Jude, Dr Hughes’ colleagues at the University of California, San Francisco, agreed to undertake the first clinical trials to evaluate the TMP-dapsone.1 The open-label study proved to be very successful.13 Subsequently, Dr Hughes was able to show that the 1 dose a week of dapsone, which was 100 percent protective in the rat model, also was effective in adults with AIDS.14 Despite the success, Dr Hughes was not satisfied that this new war had been won, his primary concern being the development of resistance of P carinii to TMP-SMX, which is used extensively worldwide and administered for life in hundreds of thousands of patients infected with HIV at risk of PCP. Hence, he began to search for anti–P carinii drugs that would act at a site other than that targeted by TMPSMX and dapsone, the folate pathway. Because TMP-SMX, dapsone, and pentamidine had shown some activity against malaria, he and his laboratory staff focused on antimalarial compounds other than folate antagonists, hoping that drugs of another class might have fewer adverse effects in AIDS patients than did the sulfonamides.1 In 1988, Dr Hughes was contacted by Dr Win Gutteridge, at the suggestion of Dr Craig Canfield, and asked if he would be interested in testing 1 of the antimalarial compounds that Gutteridge and his colleagues had been studying at Wellcome Laboratories in Beckinham, England. Dr Hughes immediately accepted the offer to test a drug in his animal model for PCP. He received very promptly from Gutteridge’s assistant, Dr Vicki Latter, a hand-delivered portion of the drug 566C80, and the studies were initiated. Two months later, on the night before he planned to leave for a meeting of the Society of Protozoology in Bristol, England, Dr Hughes completed the histologic sections of rat lungs. While at the meeting, he met with Gutteridge, Latter, and 2 young investigators, Dr Michael Rogers and Steve LaFon, both from Burroughs-Wellcome, USA. They all were impressed with the results, scribbled on a notepad:1 “in 90 percent of the animals, 566C80 prevented PCP, whereas 100 percent of the controls were infected.”15 They then planned their strategy for initiating future studies.1 Dr Hughes was able to obtain permission from the director of St. Jude to bring adults with AIDS into the pediatric clinic to perform phase I studies. Initially, his plan met with a wall of resistance based on fear. In addition to
Walter T. Hughes, MD Table 1. Drugs Identified at the St. Jude Laboratory As Being Anti–P carinii1 Year Reported
Drug
1974 1984 1986 1986 1990 1991 1991 1991 1993 1997 1997
Trimethoprim-sulfamethoxazole* Dapsone* Carbutamide Sulfonylbisformanilide Atovaquone* Erythromycin-sulfisoxazole Clarithromycin-sulfamethoxazole Azithromycin-sulfmethoxazole PS-15 (a biguanide) Mycophenolate mofetil Lasalocid
*Efficacy and safety were shown in both animal experiments and clinical trials. The other drugs and drug combinations were found effective in animals but have not been studied in humans.
hate mail and anonymous flyers that littered the hospital, threats came from donors, who threatened to withdraw their support. Many people felt that AIDS was not the sort of thing with which St. Jude should be associated. Walter Hughes did not agree—nor did Danny Thomas, the founder of the hospital, who gained support by personally announcing the program at the ground-breaking ceremony for the new research tower. His presence alone served to change the minds of many people. For the others, Dr Hughes set out on his own campaign—to educate. He had been involved in the early cases of AIDS because these patients, like those with cancer, were dying of PCP. He instantly recognized the threat posed by PCP, and his expertise was invaluable. The National Institutes of Health responded
Figure 7. Dr Walter Hughes being presented the Chancellor’s Medal from the University of Chile. University president Luis Riveros presented the award at a ceremony in recognition of Hughes’ multiple research contributions to the health and welfare of children worldwide and for his continued support of developing clinical and biomedical research programs in Chile. (Courtesy of Dr Walter Hughes.)
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with a multimillion dollar grant that was used to establish the pediatric AIDS Clinical Trial Unit, a cooperative effort among St. Jude, the Regional Medical Center at Memphis, and LeBonheur Children’s Medical Center.3 Using a tablet formulation, they were able to delineate safety and pharmacokinetics.16 Researchers at the National Institutes of Health then reported successful treatment of some PCP patients with 566C80 in an open-label study. The next step involved a multicenter, international, doubleblind study to compare the drug 566C80 with TMP-SMX for treatment of mild and moderate cases of PCP in patients with AIDS.1 The results of a study that involved 408 patients showed that 566C80, now given the generic name atovaquone, not only had overall therapeutic success similar to that of TMP-SMX, but despite being slightly less effective was also much safer than TMP-SMX.17 Two years later (1993), the Food and Drug Administration approved atovaquone. Only 41⁄2 years had elapsed since Hughes first received the compound from Latter. Dr Hughes attributes the rapid development of drugs to the corticosteroidtreated rat model, noting that in each instance results from animal experiments predicted precisely the results of clinical trials in humans.1 During the next several years, Dr Hughes and his colleagues identified several drugs with potent activity against P carinii that were being tested in clinical trials (Table 1). He then turned his attention to learning more about primary infection with P carinii, the antibody for which is acquired early in life by most healthy humans. Classification of P carinii remains problematic, and attempts to classify it as a fungus have not helped because the drugs used for PCP have no antifungal activity and antifungal drugs have no activity against P carinii. The 2 primary needs noted
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B. Lee Ligon at St. Jude, which he held from 1993 until 1998; this chair is the only pediatric AIDS research chair in the world. He also is the recipient of the Etteldorf Alumni Award (1994); the Distinguished Physician Award, Pediatric Infectious Diseases Society (1997); and the Outstanding Alumnus Award, University of Tennessee, Memphis (1997). In 1999, Hughes was awarded the Chancellor’s Medal (Medalla Rectoral), University of Chile, the highest honor given by the University of Chile (Fig 7),3 and in 2000, he received the Facultad de Medicina Award, Universidad de Chile (Chris Winston, personal communication, July 29, 2001; Dr Walter Hughes, personal communication, August 1, 2001). Dr Hughes has played a key role in establishing the St. Jude infectious diseases outreach programs to Chile, and this outreach led to the creation of an infectious diseases clinical research network that involves several Chilean sites.18 St. Jude Children’s Research Hospital has honored him with a portrait that hangs in the lobby of the building (Fig 8). Walter Hughes is grateful for the awards and other recognition, but he is quick to note that the most important
Figure 8. Photograph of the portrait of Dr Walter Hughes that hangs in the lobby of St. Jude Children’s Research Hospital. (Courtesy of Dr Walter Hughes.)
by Dr Hughes are (1) in the clinic, a single, rapid, sensitive, and specific noninvasive diagnostic test for PCP; and (2) in the laboratory, a method to cultivate P carinii in vitro indefinitely.1 And so the research continues. Today, the department’s emphasis primarily is on AIDS, and the information gleaned from the AIDS program also benefits the leukemia research.
Awards, Honors, and Accolades Dr Hughes is world-renowned in his field and has received numerous awards and other forms of recognition to that effect. He has served on the editorial boards of Pediatric Infectious Diseases and the Journal of Acquired Immune Deficiency Syndromes, as a section editor for Advances in Pediatric Infectious Diseases, and as an editorial consultant for the Report of the Committee on Infectious Diseases from the American Academy of Pediatrics (Redbook). He served as President of the Pediatric Infectious Diseases Society from 1983 to 1985, on the Executive Board of the Pediatric Infectious Diseases Society from 1980 to 1988, and as Chairman of the Committee on Infectious Diseases for the Tennessee Academy of Pediatrics from 1992 to 1997. Among his awards are the first endowed Arthur Ashe Chair in Pediatric Aids Research
Figure 9. Recent photograph of Jeanette and Walter Hughes at their home overlooking the Mississippi River on Harbortown Island, Memphis, TN. (Courtesy of Dr Walter Hughes.)
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Figure 10. The Hughes children: (L to R) Greg, Administrator, Mental Health, Delten Medical Center; Carla, Teacher, elementary-special education, Baldwin School; and Chris, transplant surgeon, Mayo Clinic. (Courtesy of Dr Walter Hughes.)
event in his life was marriage to his wife Jeanette 44 years ago (Fig 9). He considers “her charm, beauty, and intellectual superiority as [his] sustaining strength.” They have been “blessed with 3 successful children,” and he notes that “Carla is a dynamic teacher in elementary and special education, Greg is an administrator and director of a Mental Health Unit at Delta Medical Center, and Chris is a transplant surgeon at the Mayo Clinic. Only our 5 grandchildren surpass them” (Fig 10) (Dr Walter Hughes, personal communication, July 22, 2001).
Retirement Years Walter Hughes stepped down as Chairman of Pediatrics in 1995, but he has not slowed his pace in the least. He visits his office frequently, keeping in touch with the progress being made in medical research. As a man of faith since his early years, he also enjoys studying concepts of religion, and he notes that he has seen “no problem they [the principles of Christianity taught in the gospels] cannot solve if applied, whether it be at a personal, national, or global level” (Dr Walter Hughes, personal communication, July 27, 2001). In addition to these pursuits, since achieving Emeritus status, he has taken up creative writing. His first novel The Yellow Martyrs, a historical novel about the “Yellow Fever virus from the West Indies [that] came like a tornado up the Mississippi River to ignite a devastating epidemic at Port of Memphis in 1878,” was published in 2000 (Fig 11). Using the daily events chronicled by local journalists, Dr Hughes has recreated the episodes and immortalized the actual individuals, as seen and experienced through the lives of the fictional Dr Collin Austin and his aide Matt Winfrey. The novel describes the risks taken and the cour-
Figure 11. Cover of Dr Hughes’ first novel, The Yellow Martyrs. (Courtesy of Dr Walter Hughes.)
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age exhibited by various heroes and heroines as they combated a disease that reduced the flourishing river city from 45,000 to 20,000 people within a fortnight.19 Dr Hughes currently is nearing completion on a science fiction novel (Dr Walter Hughes, personal communication, August 1, 2001).
Personal Tributes Dr Walter Hughes is loved and remembered by numerous colleagues. The comments of a few of them depict the tremendous respect and fondness they have for this remarkable man, who has lived out his faith in his commitment to his family, to improving the health of others, to the responsibilities of teaching and training future generations of physicians and scientists, and to the field of pediatrics. [Dr Hughes] has led the way in improving treatment of life-threatening infections . . . His dedication to unsurpassed patient care has provided a role model for many in this institution and throughout the world. Dr Arthur Nienhuis3 He is a true leader . . . He’s always seen it before and knows what will happen. The contributions he has made to the management of PCP are unsurpassed by any other individual.” Dr Pat Flynn3 Born in the poor rural south, Walter was astonished to discover in middle age that he had been raised in a region designated below the poverty line, implying an upbringing under conditions of extreme hardship of which he was unaware. . . . Walter’s unassuming, humble, unmaterialistic, and optimistic persona disguise the depth and breadth of a man of profound intellect and integrity. A sense of and respect for scholarship reverberates through everything that he embraces. In the years that I was closely associated with him, he was a mentor of unsurpassed consistency, inspiration, kindness, and example. Although always tolerant of lesser standards in others and generous to a fault, he subjected himself to a rigorous self-discipline, reflected in the incisive, creative, and original nature of his research and the transparency of his scientific writing. He never set out consciously to set an example, but all who have been fortunate enough to be associated with him know that his work represents the epitome of scientific endeavour and integrity. His seminal contributions to the biology and treatment of Pneumocystis carinii and more recently his contribution to human immunodeficiency virus research ensure his place in medical history as a paediatrician and clinician scientist. A devoted family man and loyal friend, Walter has achieved the dual pinnacles of professional and domestic fulfillment and has done so in his own inimitable and exemplary style. Professor Richard Moxon Oxford University, UK Communicated to Ms. Chris Winston July 27, 2001 I think it is great for Walter to get recognition like this. It’s hard to know what to say. I guess I would say that his meticulous approach to animal experimentation has resulted in what has now become the global standard for the prevention of PCP. His work has without question been the most important work ever done with regards to P carinii and has prevented hundreds of thousand cases of PCP and saved innumerable lives. He has done all this with a modesty and
openness that is unfortunately becoming less and less prominent in biomedical research. I wish I could be more eloquent. Dr Frank Gigliotti University of Rochester Communicated to Ms. Chris Winston July 31, 2001 Growing up in a small town in the mountains of East Tennessee during the Great Depression, Walter Hughes set out on a career in medicine. Fortuitously, his interest gravitated toward pediatrics and infectious diseases. Rising from Instructor to full Professor in the Department of Pediatrics at the University of Louisville in 5 years is one indication of Walter’s extraordinary talent. As the first Chief of Infectious Diseases at St. Jude Children’s Research Hospital, Walter almost immediately encountered a devastating epidemic of Pneumocystis carinii pneumonia in children with leukemia. With nominal fanfare, Walter became a world-class authority on the pathogenesis of this disease and identified methods of treatment and prevention, which today continue to save untold lives. He achieved this not by dazzling molecular techniques, but rather by strictly adhering to scientific method, a work ethic second to none and keen insight into pathogenesis. So too he has been a leader in developing sound management practices for the neutropenic patient and the child infected with HIV. Throughout his career, Walter remained a gentleman, a scholar, and a devoted husband and father—always, no exceptions. Like the Mississippi River flowing alongside his home in Memphis, the fruits of Walter’s labors will just keep on rolling along, unheralded, for years and years to come. When all is said and done, it all seems fitting. Dr Jerry Shenep St. Jude Children’s Research Hospital Communicated to Ms. Chris Winston August 1, 2001 I feel honored to get a premature glimpse of the article on Dr Hughes . . . I learned things about him that I never knew, mostly his childhood years. Dr Hughes is a very private, professional person who commands a great deal of respect. In all the years I worked for him, I never saw him lose his composure. Chris Winston St. Jude Children’s Research Hospital Personal communication August 7, 2001
Acknowledgment The author thanks Dr Walter Hughes for the privilege of writing this biography and for his invaluable assistance with it. Appreciation also is extended to Chris Winston of St. Jude Children’s Research Hospital, who worked with Dr Hughes before his retirement and graciously assisted by contacting his colleagues and by providing dates, photographs, and information; to his colleagues, Drs Richard Moxon, Frank Gigliotti, and Jerry Shenap, all who responded very quickly with their comments; to Elizabeth Walker, Publications Coordinator, St. Jude Children’s Research Hospital, who helped procure photographs; to Jeff Meadows, Director of Publications and Communications, Palmer Memorial Episcopal Church, Houston, TX, who prepared the photographs for publication; and to Dr Ralph D. Feigin, who reviewed the manuscript.
References 1. Hughes WT: Pneumocystis carinii pneumonitis. Infectious Dis Clin Prac 6:379-384, 1997
Walter T. Hughes, MD 2. Pizzo PA: The Pediatric Infectious Diseases Society Annual Awards, 1997. Pediatr Infect Dis J 16:831-835, 1997 3. Vallance S: A modest man, a remarkable career: Walter Hughes, MD: A profile. Corridors Oct/Nov:6-7, 1996 4. Frenkel JK, Good JT, Shultz JA: Latent pneumocystis infection in rats, relapse, and chemotherapy. Lab Invest 15:1559, 1966 5. Hughes WT, McNabb PC, Makres TD, et al: Efficacy of trimethoprim and sulfamethoxazole in the prevention and treatment of Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother 5:289-293, 1974 6. Hughes WT, Feldman S, Sanyal SK: Treatment of Pneumocystis carinii pneumonitis with trimethoprim-sulfamethoxazole. Can Med Assoc J 112:475-505, 1975 7. Hughes WT, Feldman S, Chaudhary S, et al: Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Pediatr 92:285-292, 1978 8. Hughes WT, Kuhn S, Chaudhary S, et al: Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 297:1419-1426, 1977 9. Hughes WT: Postulates for the evaluation of adverse reactions to drugs. Clin Infect Dis 20:179-182, 1995 10. Hughes WT: Five-year absence of Pneumocystis carinii pneumonitis in a pediatric oncology center. J Infect Dis 150:305, 1984 11. Masur H, Michelis MA, Green JB, et al: An outbreak of community-acquired Pneumocystis carinii pneumonia. N Engl J Med 305:1431-1438, 1981
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12. Hughes WT, Smith BL: Efficacy of diaminodiphenylsulfone and other drugs in murine Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother 26:436-440, 1984 13. Leoung GS, Mills J, Hopewell PC, et al: Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 105:45-48, 1986 14. Hughes WT, Kennedy W, Dugdale M, et al: Prevention of Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone. Lancet 336:1066, 1990 15. Hughes WT, Gray VL, Gutteridge WE, et al: Efficacy of a hydroxynapthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother 34:225288, 1990 16. Hughes WT, Kennedy W, Shenep JL, et al: Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with antiPneumocystis carinii activity: A phase I study in human immunodeficiency virus (HIV)-infected men. J Infect Dis 163:843848, 1991 17. Hughes WT, Leong G, Kramer F, et al: Comparison of atovquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 328:1521-1527, 1992 18. Anonymous: Walter Hughes honored. Corridors February/ March:3, 2000 19. Hughes WT: The Yellow Martyrs. San Jose, CA, Writer’s Club Press, 2000. Release information, Iuniverse.com, http://www. iuniverse.com/marketplace/bookstore/book_detail.asp?isbn⫽ 0%2D595%2D13276%2D6. Accessed July 30, 2001
ith the increased prevalence of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) in children and adolescents, as well as in adults, specialists in infectious diseases have encountered numerous challenges in the diagnosis and treatment of other associated diseases, many of which pose specific risks for this particularly vulnerable population. An important opportunistic infection associated with this increased prevalence is Pneumocystis carinii pneumonia (PCP), which earlier took the lives of patients who had been cured of leukemia1 and more recently has occurred in epidemic proportions among patients with HIV and AIDS. Untreated, the disease always is fatal.1 Since his first descriptive report on PCP in 1971, Walter T. Hughes, MD, (Fig 1) has been the unequaled authority on the disease, its prevention, and its treatment. Having devoted his entire career to the battle against a disease that poses particular dangers to the immunocompromised patient, he has emerged victor, having developed both prophylactic and treatment regimens. The victories once gained for patients with leukemia, cancer, and other such diseases are now being applied to the newest population of severely vulnerable patients, those with acquired immunodeficiencies. The recipient of the Pediatric Infectious Diseases Society’s 1997 Distinguished Physician
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From the Department of Pediatrics, Baylor College of Medicine, Houston, TX. Address correspondence to B. Lee Ligon, PhD, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin, MC 3-1000, Houston, TX 77023. E-mail: [email protected] Copyright © 2001 by W.B. Saunders Company 1045-1870/01/1204-0010$35.00/0 doi:10.1053/spid.2001.28615
Award (Fig 2), Dr Hughes is the subject of this article, which seeks to honor his outstanding research accomplishments, his commitment to his profession and to his patients, and his devotion to his family, all of which find their source in his faith.
Early Childhood and Education Walter Hughes (Fig 3) was born in 1930 on a farm in southeast Tennessee to Walter and Millie Hughes. Because Cleveland, TN, was the nearest town, it was given as his place of birth, but the actual location was the family farm. Walter Hughes, Sr, inherited a lumber company from his father and grandfather, and despite having little formal education, he was able to develop the company while also farming on the side. Today, Dr Hughes remembers his father as “a remarkably honest, highly intelligent, jovial, and lovable man” (Dr Walter Hughes, personal communication, July 22, 2001 and August 3, 2001). Unfortunately, when young Walter was only 9 years old, his father died of pneumococcal pneumonia, leaving his wife to rear Walter and his 2 younger siblings. She managed remarkably well. She gave the 3 children religious and moral training at home and, without the aid of Pell grants, welfare aid, or financial scholarships, each one received a strong academic education. Dr Hughes’ brother Joe became an orthopedic surgeon in Atlanta; his sister Katherine became the wife of a prominent university professor, also in Atlanta; and as this article recounts, Dr Hughes became a renowned scientist. Her children all credit their devoted mother with providing them the resources and helping them develop the resolve needed to achieve academically (Dr Walter Hughes, personal communication, July 22,
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Figure 1. Dr Walter Hughes. (Courtesy of St. Jude Children’s Research Hospital.) 2001). She also instilled in them a strong basis for their Christian faith and appreciation for its principles (Dr Walter Hughes, personal communication, July 27, 2001).
Walter Hughes is a product of public education from kindergarten through medical school, for which he is grateful. His elementary school days date back to the time when schools were equipped with chalkboards, tablets, and no. 2 pencils. The school Walter Hughes attended also had a wind-up phonograph for classical music, which was played once a week, and it was noted for its dynamic, disciplined, and dedicated teachers. He considers this time an opportunity to learn about the real world and how to cope. During these early years, Walter encountered a distinct challenge to his education endeavors. He had a mild form of dyslexia, and his experience predated the recent recognition of the problem and the various approaches to accommodate students who have it. He discovered on his own how to deal with it by writing or rewriting everything he heard or read. The procedure is one he still uses for important topics (Dr Walter Hughes, personal communication, July 22, 2001). In high school, Walter’s interests leaned heavily toward music and other fine arts. He played the trumpet and the French horn in the band and in the orchestra, he sang in the chorus, he was president of the Thespian Society, and he had a lead in the senior play. All of his close childhood friends through high school entered various fields of music, theater, or business, but Walter Hughes chose to go another route. He notes that his decision not to pursue any of these interests as a career was fortunate because he “was never a very good musician or actor and definitely not inclined to business” (Dr Walter Hughes, personal communication, July 22, 2001 and August 1, 2001).
Medical Training and Military Service The choice of medicine for a career was not an easy one to make. He also considered the clergy, architecture, and
Figure 2. Dr Walter Hughes receiving the Distinguished Physician Award at the Annual Awards Ceremony of the Pediatric Infectious Diseases Society, 1997. (Courtesy of Dr Walter Hughes.)
Walter T. Hughes, MD
Figure 3. Walter Hughes at 3 years of age. (Courtesy of Dr Walter Hughes.)
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of cases of orophryngeal tularemia that he had studied. That paper was to change the course of his career. Although he had been considering a career in hematology, events would alter that plan and take him in another direction. While completing his training in pediatrics, Dr Hughes was drafted into the Army with an initial assignment to Korea (Fig 4). When authorities learned of Dr Hughes’ experience with tularemia, they decided instead to send him to Walter Reed Army Institute of Research Unit at Fort Detrick, MD, a highly classified research center for biological warfare, a Mecca for microbiologists. The question Dr Hughes kept asking himself was “why me?” Little time passed before he learned the reason. The Cold War was just beginning, and rumors that the Russians had learned to aerosolize Francisella tularensis, a prominent candidate for bacterial warfare that was under study for this purpose by many countries, created immense concern. Furthermore, the Department of Defense had learned that the Soviets had immunized thousands of their people against tularemia. The United States initiated a major effort for defense against tularemia at the facility in Fort Detrick, and 4 young officers (Drs Richard Hornick, Ken Vosti, Bill Burmeister, and Walter Hughes) were added to a team of senior investigators. They spent 2 years evaluating a vaccine in trials with monkeys and human volunteers. As a result of this experience, each of the 4 of them later pursued careers in infectious diseases and academic medicine (Dr Walter Hughes, personal communication, July 22, 2001 and August 1, 2001).2
Early Medical and Research Career journalism. His college aptitude tests ranked him very high in fine arts and language, but only average in science. Nonetheless, as he considered all these options, he was drawn to medicine primarily because it seemed to offer more opportunities to help people, a factor that played a strong role in the decision of a young man who had grown up with strong altruistic inclinations because of his religious background (Dr Walter Hughes, personal communication, June 22, 2001). In 1950, Dr Hughes was accepted at The University of Tennessee College of Medicine. Unlike some of his colleagues, Dr Hughes did not consider the experience fun, and he recalls it as a 3-year marathon to pass examinations. Among the demands of medical school was that he improve his skills in overcoming the dyslexia. For the primary texts, he wrote extensive abbreviations, many of which were duplicated for his classmates. He recalls that he “passed biochemistry by writing the endless structural formulas of organic compounds on rolls of toilet paper (it was free in the dorm).” Only after medical school did he become thrilled with the study of medicine (Dr Walter Hughes, personal communication, June 22, 2001). After receiving his medical degree and completing a year of rotating internships, Dr Hughes began a residency in pediatrics at the Le Bonheur Children’s Hospital in 1955. While there, he was encouraged by his chief and dedicated mentor, Dr James Ettledorf, to publish a paper on a series
After being discharged from the Army, Dr Hughes entered private practice in his hometown of Cleveland, TN. The
Figure 4. Dr Walter Hughes, Captain, US Army, 1957. (Courtesy of Dr Walter Hughes.)
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practice was very busy with wall-to-wall patients, requiring that Dr Hughes work from dawn to bedtime. This experience was invaluable to his subsequent years in academic medicine. He contends that nothing can better prepare the university professor in clinical pediatrics than a couple of years of private practice in a small town (Dr Walter Hughes, personal communication, August 1, 2001). His stay in Cleveland was short-lived. After 2 years, he left to engage in academic research in infectious diseases at the University of Louisville, where he developed an interest in what he considered “odd infections,” namely those caused by fungi. Primarily interested in the aflatoxins produced by Aspergillus species, Dr Hughes also became involved in research on the then emerging spectrum of invasive mycoses in children with cancer.2 During a remarkable tenure at Louisville, he proceeded from Instructor in 1961 to Professor in 1966. During this period, he received on 3 occasions the Most Outstanding Clinical Teacher Award, wrote a book entitled Pediatric Procedures, and established a research laboratory to study opportunistic fungi. In bedside teaching, he never allowed his students or residents to use the abbreviation LMD (local medical doctor) for the person who referred a patient. Instead, they were required to give the name of the local medical doctor. In 1968, he served as Acting Chairman of the Department and as Physician-in-chief of Children’s Hospital. The experience convinced him that his heart was in the research laboratory with infectious diseases rather than in departmental administration, and he stepped down from the post (Dr Walter Hughes, personal communication, August 1, 2001).2 A year later, he was called to a new hospital that was focusing on children with cancer and hematologic diseases.
St. Jude Children’s Research Hospital and Development of PCP Prophylaxis In 1969, Dr Hughes was invited by Donald Pinkel, MD (Fig 5), the visionary director of St. Jude Children’s Research Hospital, to join the new institution, which had been open only 7 years. Hughes is quoted as saying that: At other places I interviewed they took me to fancy restaurants. When Dr Pinkel picked me up at the airport, he brought me straight to St. Jude and we spent 3 hours or so going over the kind of research they were doing. Then, he drove me to his house for hot dogs and beer. At 2 AM, I got back to my hotel and he told me he’d pick me up at 7 AM so we could talk some more. By the end of that day, I was completely caught up in the philosophy of St. Jude.3
Even in its early years, the hospital was gaining a reputation for outstanding research. Under Dr Pinkel’s direction, a curative therapy for acute lymphocytic leukemia, until then a uniformly fatal malignancy, had been discovered. Dr Hughes accepted the invitation and joined the new faculty of clinical investigators and basic scientists who were focusing on catastrophic diseases of children. He was Chief of the Infectious Diseases Service, which comprised 1 person—Walter Hughes! As the sole staff member, Dr
Figure 5. Dr Donald Pinkel. (Courtesy of St. Jude Children’s Research Hospital.)
Hughes made rounds every day, saw patients every day, and was on call every day. His daily encounters with children showed him that their valiant battles against their diseases left them with no defense against infections.3 During the next 8 years, Dr Hughes expanded the Service, which soon grew to a Division, and then to a Department, and he was in the chairmanship role again. When Dr Hughes came to St. Jude, his particular focus of research was in mycology, specifically the potent carcinogenic aflatoxins of Aspergilus flavus.1,2 This work was interrupted by the occurrence of an emerging infection of great magnitude at St. Jude (Dr Walter Hughes, personal communication, August 1, 2001). Numerous cases of pneumonia caused by P carinii were occurring among an increasing population of cancer patients. He had never seen a case of PCP, but he was about to become quickly engulfed in its devastating consequences. By the early 1970s, they were seeing 30 to 40 cases a year, and Dr Hughes was being taught by patients, oncologists, and pathologists about the disease that was taking the lives of patients cured of leukemia. At the time, the only effective therapy for PCP was pentamidine isethionate, which had to be ordered from the Parasitic Disease Branch at the
Walter T. Hughes, MD Centers for Disease Control and Prevention (CDC) on a case-by-case basis. The drug, which had to be administered intramuscularly, had adverse reactions in 70 to 80 percent of patients.1 The obvious need for better therapeutic drugs led Dr Hughes to establish an animal model for PCP in his laboratory, following the method devised by Dr Jack Frenkel in Kansas City.4 They quickly and easily provoked PCP in rats by simply administering cortisone acetate. The pneumonitis, which occurred in 90 to 100 percent of the animals, was remarkably similar to that in humans. The first vaccine was used to immunize the rats, which attained high antibody titers. However, after the animals were challenged with cortisone acetate, all of them died. Dr Hughes later noted that the deaths were disappointing, but not necessarily surprising because they had already found high antibody titers in cancer patients who had developed PCP.1 After trying several other compounds, Dr Hughes and his team turned to a combination of trimethoprim and sulfamethoxazole (TMP-SMX)2 after learning that evidence existed indicating that the folate antagonist fansidar was effective in treating PCP in Iranian infants. Dr Hughes also had heard from his former chief, Alex Steigman, MD, of its use as an antibiotic in Europe. Because the combination was not marketed in the United States, Dr Hughes contacted 2 pharmaceutical companies and requested a small supply to test in the animal model. One of the companies responded by providing a limited amount, and St. Jude provided the rats. The study, which cost a total of approximately $300,1 showed striking therapeutic and prophylactic effects.5 Immediately, a pilot clinical trial in patients with mild PCP was undertaken, and the drug administered orally proved to be effective.6 A randomized clinical trial comparing oral TMP-SMX with intramuscular pentamidine in patients with PCP of any severity showed a therapeutic success rate of 75 percent for pentamidine and 77 percent for TMP-SMX; the latter also lacked significant adverse effects.1,7 These successes indicated that development of chemoprophylaxis for PCP was a reasonable possibility, and in 1974, Dr Hughes and his team began a double-blind, placebo-controlled randomized study in children with cancer at high risk for PCP, 80 in each group. Because halfway through the study the overall incidence of PCP had been reduced 50 percent, strongly suggesting success, Dr Hughes’ oncology colleagues began to pressure him to stop the study, break the code, and place all the patients on TMP-SMX. However, Dr Hughes had reservations about doing so. One concern was that the broad-spectrum antibiotic activity of TMP-SMX might result in the replacement of PCP with a concomitant increase in other infections such as candidiasis and Pseudomonas aeruginosa infections. Another concern was that the antifolate activity might diminish host folate stores when given along with drugs such as methotrexate. Unless these and other questions were addressed, he feared that physicians might be hesitant to institute TMP-SMX prophylaxis and further placebo-controlled studies for adverse effects could never be justified because
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of demonstrated efficacy for PCP prophylaxis1 (Dr Walter Hughes, personal communication, August 1, 2001). The controversy became so intense that the issue came under review and was put to a vote by the faculty, which was favorable for continuing the study until completion.1 The final results showed unequivocally the value of prophylaxis: 21 percent of the placebo group had PCP, whereas none of the treated group had PCP infection, nor was the microbial flora significantly affected. The drug was determined to be safe.8 Dr Hughes (Fig 6) noted later that the study also revealed another lesson often overlooked in evaluating the true side effects of drugs: adverse effects occurred with equal frequency in the control and treated groups and 2 patients who had been removed from the study because of severe rash and neutropenia later, when the code was broken, were found to have been part of the placebo group.1,9 Since that study, all patients with leukemia treated at St. Jude have been placed on TMP-SMX prophylaxis, with the result that no cases of PCP occurred during the next 5 years10 and only an occasional sporadic case occurred during the course of the next 20 years, despite an increase in the number of high-risk patients and more intensive chemotherapy for cancer1 (Dr Walter Hughes, personal communication, August 1, 2001).
Figure 6. Dr Walter Hughes in his laboratory at St. Jude Children’s Research Hospital in 1976. (Courtesy of St. Jude Children’s Research Hospital.)
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Johns Hopkins University School of Medicine and the Call to Address AIDS
Research for Alternative Medications for PCP
In 1977, Dr Hughes “was lured away from Memphis”3 to Baltimore, where he accepted the post of Director of the Division of Infectious Diseases in Pediatrics and Eudowood Professor of Pediatrics at Johns Hopkins University School of Medicine. Work on PCP continued, but at a low level, primarily because the importance of P carinii was not evident. An unusual event led to new research and, ultimately, to Hughes’ return to St. Jude. In 1981, he was speaking at Grand Rounds at the University of Pittsburgh. At the completion of his lecture, Dr Hughes was handed a note marked “urgent.” It was from Dr Jeffry Green at New York University Medical Center; Dr Green was asking for advice in treating a young man who was suffering from PCP and an unidentified underlying disease. Although TMP-SMX had been started and the patient had shown some improvement initially, an exfoliative rash and neutropenia had developed. Dr Hughes recommended that the medication be changed to pentamidine and requested that Dr Green let him know the outcome. Several weeks later, Dr Hughes received a letter from Dr Green, who provided a detailed report charting the patient’s course until recovery. Included in the correspondence was a comment that the patient was the fifth case of P carinii pneumonitis Dr Green had seen among young homosexuals at their institution and that every case had occurred within a short span of time. Dr Green suggested that perhaps the homosexual population had, as he put it, a “heretofore unrecognized acquired immunodeficiency.”1 The findings of Green and colleagues led to the publication of the classic paper, coauthored with Henry Masur, describing the first cases of AIDS from the east coast.11 In many ways, these cases of PCP were responsible for the identification of AIDS in the United States; they also account for the exaggerated rate of adverse effects that later were reported on TMP-SMX1 (Dr Walter Hughes, personal communication, August 1, 2001). The increased incidences of adverse reactions to TMPSMX experienced by patients with AIDS led to demands for more dosages of pentamidine, and the supply at the CDC soon was diminished. Much to the surprise and concern of the CDC staff, May and Baker, the manufacturers in England, had stopped making pentamidine and no other source was available anywhere in the world. Considering the limited supply of pentamidine and the adverse effects of TMP-SMX in patients with AIDS, Dr Hughes went back to work on an animal model to search for more drugs. His decision involved a return to St. Jude in 1981, and a major factor in leaving Baltimore was his family’s love of Memphis as a place to live. Dr Hughes holds Hopkins close and has continued to serve on the faculty as lecturer in pediatrics for the past 20 years (Dr Walter Hughes, personal communication, August 1, 2001).
On his return to St. Jude, Dr Hughes resumed the chairmanship of the Department of Infectious Diseases, a position he held until 1995. He recalled that “it was very reminiscent of 1969 because while I was gone everyone else left too. Here I was at St. Jude again with a faculty of 1.”3 He quickly set to work recruiting a new staff, 1 of whom was Dr Jerry Shenep, who always felt a sense of team spirit working alongside Dr Hughes.3 By 1984, Dr Hughes was able to report animal experiments showing that diamino-diphenyl sulfone (dapsone) had potent activity against P carinii and that the activity could be enhanced synergistically with TMP.12 Because he had no patients with PCP at St. Jude, Dr Hughes’ colleagues at the University of California, San Francisco, agreed to undertake the first clinical trials to evaluate the TMP-dapsone.1 The open-label study proved to be very successful.13 Subsequently, Dr Hughes was able to show that the 1 dose a week of dapsone, which was 100 percent protective in the rat model, also was effective in adults with AIDS.14 Despite the success, Dr Hughes was not satisfied that this new war had been won, his primary concern being the development of resistance of P carinii to TMP-SMX, which is used extensively worldwide and administered for life in hundreds of thousands of patients infected with HIV at risk of PCP. Hence, he began to search for anti–P carinii drugs that would act at a site other than that targeted by TMPSMX and dapsone, the folate pathway. Because TMP-SMX, dapsone, and pentamidine had shown some activity against malaria, he and his laboratory staff focused on antimalarial compounds other than folate antagonists, hoping that drugs of another class might have fewer adverse effects in AIDS patients than did the sulfonamides.1 In 1988, Dr Hughes was contacted by Dr Win Gutteridge, at the suggestion of Dr Craig Canfield, and asked if he would be interested in testing 1 of the antimalarial compounds that Gutteridge and his colleagues had been studying at Wellcome Laboratories in Beckinham, England. Dr Hughes immediately accepted the offer to test a drug in his animal model for PCP. He received very promptly from Gutteridge’s assistant, Dr Vicki Latter, a hand-delivered portion of the drug 566C80, and the studies were initiated. Two months later, on the night before he planned to leave for a meeting of the Society of Protozoology in Bristol, England, Dr Hughes completed the histologic sections of rat lungs. While at the meeting, he met with Gutteridge, Latter, and 2 young investigators, Dr Michael Rogers and Steve LaFon, both from Burroughs-Wellcome, USA. They all were impressed with the results, scribbled on a notepad:1 “in 90 percent of the animals, 566C80 prevented PCP, whereas 100 percent of the controls were infected.”15 They then planned their strategy for initiating future studies.1 Dr Hughes was able to obtain permission from the director of St. Jude to bring adults with AIDS into the pediatric clinic to perform phase I studies. Initially, his plan met with a wall of resistance based on fear. In addition to
Walter T. Hughes, MD Table 1. Drugs Identified at the St. Jude Laboratory As Being Anti–P carinii1 Year Reported
Drug
1974 1984 1986 1986 1990 1991 1991 1991 1993 1997 1997
Trimethoprim-sulfamethoxazole* Dapsone* Carbutamide Sulfonylbisformanilide Atovaquone* Erythromycin-sulfisoxazole Clarithromycin-sulfamethoxazole Azithromycin-sulfmethoxazole PS-15 (a biguanide) Mycophenolate mofetil Lasalocid
*Efficacy and safety were shown in both animal experiments and clinical trials. The other drugs and drug combinations were found effective in animals but have not been studied in humans.
hate mail and anonymous flyers that littered the hospital, threats came from donors, who threatened to withdraw their support. Many people felt that AIDS was not the sort of thing with which St. Jude should be associated. Walter Hughes did not agree—nor did Danny Thomas, the founder of the hospital, who gained support by personally announcing the program at the ground-breaking ceremony for the new research tower. His presence alone served to change the minds of many people. For the others, Dr Hughes set out on his own campaign—to educate. He had been involved in the early cases of AIDS because these patients, like those with cancer, were dying of PCP. He instantly recognized the threat posed by PCP, and his expertise was invaluable. The National Institutes of Health responded
Figure 7. Dr Walter Hughes being presented the Chancellor’s Medal from the University of Chile. University president Luis Riveros presented the award at a ceremony in recognition of Hughes’ multiple research contributions to the health and welfare of children worldwide and for his continued support of developing clinical and biomedical research programs in Chile. (Courtesy of Dr Walter Hughes.)
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with a multimillion dollar grant that was used to establish the pediatric AIDS Clinical Trial Unit, a cooperative effort among St. Jude, the Regional Medical Center at Memphis, and LeBonheur Children’s Medical Center.3 Using a tablet formulation, they were able to delineate safety and pharmacokinetics.16 Researchers at the National Institutes of Health then reported successful treatment of some PCP patients with 566C80 in an open-label study. The next step involved a multicenter, international, doubleblind study to compare the drug 566C80 with TMP-SMX for treatment of mild and moderate cases of PCP in patients with AIDS.1 The results of a study that involved 408 patients showed that 566C80, now given the generic name atovaquone, not only had overall therapeutic success similar to that of TMP-SMX, but despite being slightly less effective was also much safer than TMP-SMX.17 Two years later (1993), the Food and Drug Administration approved atovaquone. Only 41⁄2 years had elapsed since Hughes first received the compound from Latter. Dr Hughes attributes the rapid development of drugs to the corticosteroidtreated rat model, noting that in each instance results from animal experiments predicted precisely the results of clinical trials in humans.1 During the next several years, Dr Hughes and his colleagues identified several drugs with potent activity against P carinii that were being tested in clinical trials (Table 1). He then turned his attention to learning more about primary infection with P carinii, the antibody for which is acquired early in life by most healthy humans. Classification of P carinii remains problematic, and attempts to classify it as a fungus have not helped because the drugs used for PCP have no antifungal activity and antifungal drugs have no activity against P carinii. The 2 primary needs noted
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B. Lee Ligon at St. Jude, which he held from 1993 until 1998; this chair is the only pediatric AIDS research chair in the world. He also is the recipient of the Etteldorf Alumni Award (1994); the Distinguished Physician Award, Pediatric Infectious Diseases Society (1997); and the Outstanding Alumnus Award, University of Tennessee, Memphis (1997). In 1999, Hughes was awarded the Chancellor’s Medal (Medalla Rectoral), University of Chile, the highest honor given by the University of Chile (Fig 7),3 and in 2000, he received the Facultad de Medicina Award, Universidad de Chile (Chris Winston, personal communication, July 29, 2001; Dr Walter Hughes, personal communication, August 1, 2001). Dr Hughes has played a key role in establishing the St. Jude infectious diseases outreach programs to Chile, and this outreach led to the creation of an infectious diseases clinical research network that involves several Chilean sites.18 St. Jude Children’s Research Hospital has honored him with a portrait that hangs in the lobby of the building (Fig 8). Walter Hughes is grateful for the awards and other recognition, but he is quick to note that the most important
Figure 8. Photograph of the portrait of Dr Walter Hughes that hangs in the lobby of St. Jude Children’s Research Hospital. (Courtesy of Dr Walter Hughes.)
by Dr Hughes are (1) in the clinic, a single, rapid, sensitive, and specific noninvasive diagnostic test for PCP; and (2) in the laboratory, a method to cultivate P carinii in vitro indefinitely.1 And so the research continues. Today, the department’s emphasis primarily is on AIDS, and the information gleaned from the AIDS program also benefits the leukemia research.
Awards, Honors, and Accolades Dr Hughes is world-renowned in his field and has received numerous awards and other forms of recognition to that effect. He has served on the editorial boards of Pediatric Infectious Diseases and the Journal of Acquired Immune Deficiency Syndromes, as a section editor for Advances in Pediatric Infectious Diseases, and as an editorial consultant for the Report of the Committee on Infectious Diseases from the American Academy of Pediatrics (Redbook). He served as President of the Pediatric Infectious Diseases Society from 1983 to 1985, on the Executive Board of the Pediatric Infectious Diseases Society from 1980 to 1988, and as Chairman of the Committee on Infectious Diseases for the Tennessee Academy of Pediatrics from 1992 to 1997. Among his awards are the first endowed Arthur Ashe Chair in Pediatric Aids Research
Figure 9. Recent photograph of Jeanette and Walter Hughes at their home overlooking the Mississippi River on Harbortown Island, Memphis, TN. (Courtesy of Dr Walter Hughes.)
Walter T. Hughes, MD
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Figure 10. The Hughes children: (L to R) Greg, Administrator, Mental Health, Delten Medical Center; Carla, Teacher, elementary-special education, Baldwin School; and Chris, transplant surgeon, Mayo Clinic. (Courtesy of Dr Walter Hughes.)
event in his life was marriage to his wife Jeanette 44 years ago (Fig 9). He considers “her charm, beauty, and intellectual superiority as [his] sustaining strength.” They have been “blessed with 3 successful children,” and he notes that “Carla is a dynamic teacher in elementary and special education, Greg is an administrator and director of a Mental Health Unit at Delta Medical Center, and Chris is a transplant surgeon at the Mayo Clinic. Only our 5 grandchildren surpass them” (Fig 10) (Dr Walter Hughes, personal communication, July 22, 2001).
Retirement Years Walter Hughes stepped down as Chairman of Pediatrics in 1995, but he has not slowed his pace in the least. He visits his office frequently, keeping in touch with the progress being made in medical research. As a man of faith since his early years, he also enjoys studying concepts of religion, and he notes that he has seen “no problem they [the principles of Christianity taught in the gospels] cannot solve if applied, whether it be at a personal, national, or global level” (Dr Walter Hughes, personal communication, July 27, 2001). In addition to these pursuits, since achieving Emeritus status, he has taken up creative writing. His first novel The Yellow Martyrs, a historical novel about the “Yellow Fever virus from the West Indies [that] came like a tornado up the Mississippi River to ignite a devastating epidemic at Port of Memphis in 1878,” was published in 2000 (Fig 11). Using the daily events chronicled by local journalists, Dr Hughes has recreated the episodes and immortalized the actual individuals, as seen and experienced through the lives of the fictional Dr Collin Austin and his aide Matt Winfrey. The novel describes the risks taken and the cour-
Figure 11. Cover of Dr Hughes’ first novel, The Yellow Martyrs. (Courtesy of Dr Walter Hughes.)
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B. Lee Ligon
age exhibited by various heroes and heroines as they combated a disease that reduced the flourishing river city from 45,000 to 20,000 people within a fortnight.19 Dr Hughes currently is nearing completion on a science fiction novel (Dr Walter Hughes, personal communication, August 1, 2001).
Personal Tributes Dr Walter Hughes is loved and remembered by numerous colleagues. The comments of a few of them depict the tremendous respect and fondness they have for this remarkable man, who has lived out his faith in his commitment to his family, to improving the health of others, to the responsibilities of teaching and training future generations of physicians and scientists, and to the field of pediatrics. [Dr Hughes] has led the way in improving treatment of life-threatening infections . . . His dedication to unsurpassed patient care has provided a role model for many in this institution and throughout the world. Dr Arthur Nienhuis3 He is a true leader . . . He’s always seen it before and knows what will happen. The contributions he has made to the management of PCP are unsurpassed by any other individual.” Dr Pat Flynn3 Born in the poor rural south, Walter was astonished to discover in middle age that he had been raised in a region designated below the poverty line, implying an upbringing under conditions of extreme hardship of which he was unaware. . . . Walter’s unassuming, humble, unmaterialistic, and optimistic persona disguise the depth and breadth of a man of profound intellect and integrity. A sense of and respect for scholarship reverberates through everything that he embraces. In the years that I was closely associated with him, he was a mentor of unsurpassed consistency, inspiration, kindness, and example. Although always tolerant of lesser standards in others and generous to a fault, he subjected himself to a rigorous self-discipline, reflected in the incisive, creative, and original nature of his research and the transparency of his scientific writing. He never set out consciously to set an example, but all who have been fortunate enough to be associated with him know that his work represents the epitome of scientific endeavour and integrity. His seminal contributions to the biology and treatment of Pneumocystis carinii and more recently his contribution to human immunodeficiency virus research ensure his place in medical history as a paediatrician and clinician scientist. A devoted family man and loyal friend, Walter has achieved the dual pinnacles of professional and domestic fulfillment and has done so in his own inimitable and exemplary style. Professor Richard Moxon Oxford University, UK Communicated to Ms. Chris Winston July 27, 2001 I think it is great for Walter to get recognition like this. It’s hard to know what to say. I guess I would say that his meticulous approach to animal experimentation has resulted in what has now become the global standard for the prevention of PCP. His work has without question been the most important work ever done with regards to P carinii and has prevented hundreds of thousand cases of PCP and saved innumerable lives. He has done all this with a modesty and
openness that is unfortunately becoming less and less prominent in biomedical research. I wish I could be more eloquent. Dr Frank Gigliotti University of Rochester Communicated to Ms. Chris Winston July 31, 2001 Growing up in a small town in the mountains of East Tennessee during the Great Depression, Walter Hughes set out on a career in medicine. Fortuitously, his interest gravitated toward pediatrics and infectious diseases. Rising from Instructor to full Professor in the Department of Pediatrics at the University of Louisville in 5 years is one indication of Walter’s extraordinary talent. As the first Chief of Infectious Diseases at St. Jude Children’s Research Hospital, Walter almost immediately encountered a devastating epidemic of Pneumocystis carinii pneumonia in children with leukemia. With nominal fanfare, Walter became a world-class authority on the pathogenesis of this disease and identified methods of treatment and prevention, which today continue to save untold lives. He achieved this not by dazzling molecular techniques, but rather by strictly adhering to scientific method, a work ethic second to none and keen insight into pathogenesis. So too he has been a leader in developing sound management practices for the neutropenic patient and the child infected with HIV. Throughout his career, Walter remained a gentleman, a scholar, and a devoted husband and father—always, no exceptions. Like the Mississippi River flowing alongside his home in Memphis, the fruits of Walter’s labors will just keep on rolling along, unheralded, for years and years to come. When all is said and done, it all seems fitting. Dr Jerry Shenep St. Jude Children’s Research Hospital Communicated to Ms. Chris Winston August 1, 2001 I feel honored to get a premature glimpse of the article on Dr Hughes . . . I learned things about him that I never knew, mostly his childhood years. Dr Hughes is a very private, professional person who commands a great deal of respect. In all the years I worked for him, I never saw him lose his composure. Chris Winston St. Jude Children’s Research Hospital Personal communication August 7, 2001
Acknowledgment The author thanks Dr Walter Hughes for the privilege of writing this biography and for his invaluable assistance with it. Appreciation also is extended to Chris Winston of St. Jude Children’s Research Hospital, who worked with Dr Hughes before his retirement and graciously assisted by contacting his colleagues and by providing dates, photographs, and information; to his colleagues, Drs Richard Moxon, Frank Gigliotti, and Jerry Shenap, all who responded very quickly with their comments; to Elizabeth Walker, Publications Coordinator, St. Jude Children’s Research Hospital, who helped procure photographs; to Jeff Meadows, Director of Publications and Communications, Palmer Memorial Episcopal Church, Houston, TX, who prepared the photographs for publication; and to Dr Ralph D. Feigin, who reviewed the manuscript.
References 1. Hughes WT: Pneumocystis carinii pneumonitis. Infectious Dis Clin Prac 6:379-384, 1997
Walter T. Hughes, MD 2. Pizzo PA: The Pediatric Infectious Diseases Society Annual Awards, 1997. Pediatr Infect Dis J 16:831-835, 1997 3. Vallance S: A modest man, a remarkable career: Walter Hughes, MD: A profile. Corridors Oct/Nov:6-7, 1996 4. Frenkel JK, Good JT, Shultz JA: Latent pneumocystis infection in rats, relapse, and chemotherapy. Lab Invest 15:1559, 1966 5. Hughes WT, McNabb PC, Makres TD, et al: Efficacy of trimethoprim and sulfamethoxazole in the prevention and treatment of Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother 5:289-293, 1974 6. Hughes WT, Feldman S, Sanyal SK: Treatment of Pneumocystis carinii pneumonitis with trimethoprim-sulfamethoxazole. Can Med Assoc J 112:475-505, 1975 7. Hughes WT, Feldman S, Chaudhary S, et al: Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Pediatr 92:285-292, 1978 8. Hughes WT, Kuhn S, Chaudhary S, et al: Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 297:1419-1426, 1977 9. Hughes WT: Postulates for the evaluation of adverse reactions to drugs. Clin Infect Dis 20:179-182, 1995 10. Hughes WT: Five-year absence of Pneumocystis carinii pneumonitis in a pediatric oncology center. J Infect Dis 150:305, 1984 11. Masur H, Michelis MA, Green JB, et al: An outbreak of community-acquired Pneumocystis carinii pneumonia. N Engl J Med 305:1431-1438, 1981
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12. Hughes WT, Smith BL: Efficacy of diaminodiphenylsulfone and other drugs in murine Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother 26:436-440, 1984 13. Leoung GS, Mills J, Hopewell PC, et al: Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med 105:45-48, 1986 14. Hughes WT, Kennedy W, Dugdale M, et al: Prevention of Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone. Lancet 336:1066, 1990 15. Hughes WT, Gray VL, Gutteridge WE, et al: Efficacy of a hydroxynapthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother 34:225288, 1990 16. Hughes WT, Kennedy W, Shenep JL, et al: Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with antiPneumocystis carinii activity: A phase I study in human immunodeficiency virus (HIV)-infected men. J Infect Dis 163:843848, 1991 17. Hughes WT, Leong G, Kramer F, et al: Comparison of atovquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 328:1521-1527, 1992 18. Anonymous: Walter Hughes honored. Corridors February/ March:3, 2000 19. Hughes WT: The Yellow Martyrs. San Jose, CA, Writer’s Club Press, 2000. Release information, Iuniverse.com, http://www. iuniverse.com/marketplace/bookstore/book_detail.asp?isbn⫽ 0%2D595%2D13276%2D6. Accessed July 30, 2001