TENNESSEE HEALTH CARE HALL OF FAME NOMINEE WALTER HUGHES

NOMINEE INFORMATION (2023)

NAME: Walter Hughes

IS THE NOMINEE LIVING OR DECEASED: Deceased

EMAIL: ceo@stjude.org

COMPANY: St. Jude Children's Research Hospital

PHONE NUMBER: (901) 595-3301

ADDRESS: 262 Danny Thomas Pl, MS 272 Memphis, Tennessee, 38105

NOMINEE BORN, LIVED OR WORKED IN TENNESSEE?: Born, Lived, Worked

Nominator Information

NAME: James Downing COMPANY: St. Jude Children's Research Hospital

EMAIL: ceo@stjude.org

PHONE NUMBER: (901) 595-3301

ADDRESS: 262 Danny Thomas Pl, MS 272 Memphis, Tennessee, 38105

RELATIONSHIP TO NOMINEE: Former colleague

DESCRIBE THE NOMINEE: Walter Hughes, MD, was a world leader in pediatric infectious diseases. As one of the first physicians to specialize in pediatric infectious diseases, he established the Department of Infectious Diseases at St. Jude Children’s Research Hospital. He served as the department’s chair from 1969–77 and 1981–95.

Dr. Hughes led the work identifying Pneumocystis pneumonia (PCP) as a life-threatening infection in pediatric cancer patients. His discovery of a drug combination to prevent and treat PCP saved countless lives of childhood cancer patients.

When the HIV/AIDS epidemic began, Dr. Hughes’ work helped identify one of the first treatments. During those early years, hundreds of children contracted the virus through blood transfusions or mother-to-infant transmission. Dr. Hughes proposed a clinical program at St. Jude dedicated to HIV/AIDS, which led to the organization declaring the disease a pediatric catastrophic disease. The organization established a pediatric clinical trials unit, and the institution’s work in HIV/AIDS continues today.

Dr. Hughes authored more than 500 articles in peer-reviewed journals and medical textbooks. In addition, he was a founding member and the first president of the Pediatric Infectious Diseases Society of America. He was a respected teacher, mentor and researcher who shared his knowledge, wisdom and clinical experience with trainees, early-career scientists and students throughout his career.

PROVIDE A SUMMARY OF THE NOMINEE'S WORK: Dr. Hughes earned his medical degree at the University of Tennessee College of Medicine (1950-1954) and completed his training at Le Bonheur Children’s Hospital (1955-1957). After serving in the U.S. Army Medical Corps at the Walter Reed Army Institute of Research at Fort Detrick, Maryland, he went into private practice in Cleveland, Tenn. He later joined the University of Louisville School of Medicine (19611968), where he rose through the ranks and eventually became Physician-in-Chief at Louisville Children’s Hospital. He received the Outstanding Clinical Faculty Award in 1962, 1963 and 1967. He joined St. Jude Children’s Research Hospital in 1969 and became the institution’s founding chair of the Department of Infectious Diseases. He also served as a professor of pediatrics at the University of Tennessee College of Medicine during that time. In 1977, he accepted the position of division head of Pediatric Infectious Diseases at John Hopkins University School of Medicine and was named the endowed Eudowood Professor of Pediatrics. He returned to St. Jude in 1981 to head the Infectious Diseases Department again until his retirement in 1998.

Dr. Hughes was the co-founder and first elected president of the Pediatric Infectious Diseases Society of America, serving from 1983 to 1985. He was a member of the organization’s executive board from 1980 to 1988. From 1992 to 1997, he was the chairman of the committee on Infectious Diseases for the Tennessee Academy of Pediatrics.

He was the inaugural Arthur Ashe Chair of Excellence for Pediatric AIDS (1993-1998), a recipient of the Etteldorf Alumni Award (1994), and named an Outstanding Alumnus for University of Tennessee, Memphis (1997). He received the Distinguished Physician Award from the Pediatric Infectious Diseases Society (1997), which recognizes a pediatrician with a distinguished career in pediatric infectious diseases marked by significant contributions, including those as a clinician, educator, or investigator. In 2021, the award was renamed the Walter T. Hughes Distinguished Physician Award in honor of Dr. Hughes.

In 2001, his collective work regarding the understanding, prevention and treatment of Pneumocystis (PCP) in pediatric cancer patients and later in adults with HIV/AIDS led to his nomination for the Lasker Award.

Dr. Hughes 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.

A prolific writer throughout his life, Dr. Hughes authored more than 500 articles in peer-reviewed journals and medical textbooks and published seven books, including On Hallowed Ground: St. Jude Children’s Research Hospital and From Wales to Pneumocystis and AIDS, a memoir.

PLEASE PROVIDE INFORMATION TO SPEAK TO THE FOLLOWING POINTS:

A true Tennessee son, Dr. Hughes rose from humble beginnings to become a world leader in pediatric infectious diseases. As one of the first physicians to specialize in the field, he helped establish a dedicated department at St. Jude Children’s Research Hospital and served as the department’s chair from 1969–77 and 1981–95.

Dr. Hughes led the work that identified Pneumocystis pneumonia (PCP) as a life-threatening infection in pediatric cancer patients and discovered a curative treatment. In the early 1970s, children with cancer were being successfully treated for leukemia, which was considered incurable a decade earlier. Unfortunately, many of these patients had weakened immune systems caused by their cancer treatment. Because their bodies couldn’t fight off PCP, 30-40 children a year were dying from infection. Once Dr. Hughes identified that it was PCP that was the culprit, he got to work on finding a safe and effective cure for the young patients.

His research led to the discovery and development of trimethoprim and sulfamethoxazole (TMP-SMX), a drug combination that could prevent and treat PCP. His work ultimately saved countless lives of childhood cancer patients. The clinical trial of TMP-SMX found it was effective with no side effects, and the results were later published in the New England Journal of Medicine. Within a short time, the incidence of PCP in St. Jude patients dropped to zero, significantly improving the cure rate for pediatric acute lymphoblastic leukemia.

In the early 1980s, PCP was discovered in another population—young men with a yet-unidentified immune disorder. Dr. Hughes was called to consult on these initial cases and shared his work with TMP-SMX and other treatments. During those early years of the HIV/AIDS epidemic, hundreds of children were contracting the virus through blood transfusions or from mother-to-infant transmission. Dr. Hughes proposed a clinical program at St. Jude dedicated to HIV/AIDS, which led to the organization declaring the disease a pediatric catastrophic disease. This led to hate mail and threats by donors to pull their funding of the hospital. Instead of caving to public opinion, Dr. Hughes began an education campaign. The National Institutes of Health awarded his work with a multimillion-dollar grant to establish the Pediatric AIDS Clinical Trial Unit, a collaboration among St. Jude, the Regional Medical Center at Memphis and LeBonheur Children’s Hospital. Today, St. Jude continues to support HIV/AIDS research through a broad, dedicated team of clinical, psychosocial, and research professionals; conduct clinical trials; provides community support and education; and offers continuity of HIV care from childhood to 24 years of age, in which they are then transitioned to an adult provider.

Dr. Hughes authored more than 500 articles in peer-reviewed journals and medical textbooks. In addition, Dr. Hughes was the co-founder and first elected president of the Pediatric Infectious Diseases Society of America. He was a respected teacher, mentor and researcher who shared his knowledge, wisdom and clinical experience with trainees, early career scientists and students throughout his career.

“I was awed by his scope of knowledge and the drive to impart it to young trainees. He remained a part of Infectious Diseases clinical rounds well after stepping down from chair, and I will always remember that each clinical question spawned a story that made his vast clinical knowledge stick with us,” said Elaine Tuomanen, MD, former chair of St. Jude Infectious Diseases Department and current director of the Children’s Infection Defense Center. “His legacy will shape the entire Pediatric Infectious Diseases Society for many decades to come.”

“In addition to being brilliant, Walter was kind and generous to all. He was an outstanding mentor for me during my training and as a young faculty member. I am extremely grateful for the opportunity,” said Pat Flynn, MD, Arthur Ashe Chair in Pediatric AIDS Research and former deputy clinical director at St.Jude.

“Walter’s seminal research was creative and meticulous. His dedication to patient care, teaching and mentoring was unsurpassed and provided a model for many at St. Jude and around the world. He was kind, humble and unassuming, a great leader with profound intellect and integrity,” said Ching-Hon Pui, MD, former St. Jude Oncology Chair and Tennessee Health Care Hall of Fame 2022 inductee.

“He was a respected teacher, mentor, and researcher who, through charming stories and wit, continuedto share a wealth of clinical experience with St. Jude trainees during his tenure as an emeritus professor. Dr. Hughes may have been soft-spoken, but those around him knew to listen because what he had to say was reliably important and valued by colleagues.” Flynn P, Tuomanen E. In Memorium: Dr Walter Hughes, MD. J Pediatric Infect Dis Soc. 2021 Sep 7;10(12):1096. doi: 10.1093/jpids/piab084.

PMCID: PMC8719614.

March 4, 2023

To whom it may concern:

I am pleased to enthusiastically support the nomination of Walter T. Hughes, M.D., for inclusion into the Tennessee Health Care Hall of Fame. Dr. Hughes, a distinguished alumnus of the University of Tennessee College of Medicine, was St. Jude Children’s Research Hospital’s (SJCRH) first and founding chairman of its Department of Infectious Disease, where he maintained his appointment from 1969-1977 and from 19811998. Dr. Hughes recognized that many children at SCJRH with acute leukemias being treated with immunosuppressive chemotherapy succumbed to an adventitious airborne fungal pneumonia rather than from their cancers. Virtually singlehandedly, Dr. Hughes identified a drug combination that cured the disease in an animal model, advanced the use of these drugs in curative and prophylactic clinical trials at SJCRH, and thereby established a therapy eventually adopted worldwide in the treatment of cancer patients and others with acquired immunodeficiencies, including AIDS. I outline the history of Dr. Hughes’ major contributions to science and medicine in the paragraphs that follow:

“Interstitial plasma cell pneumonia” was first identified in the 1930s and 1940s in infants and was recognized in the mid-1950s to be caused by Pneumocystis carinii, an opportunistic fungus. P. carinii pneumonia (PCP) invariably occurs in immunosuppressed patients, including those with congenital immunodeficiencies, those receiving immunosuppressive therapy for neoplastic disease or organ transplantation, or patients with AIDS The organism is ubiquitous and, based on antibody studies, it appears that most people are exposed early in life. P. carinii cannot be propagated in vitro, and apart from human clinical experience, its pathogenic effects were first studied in rats that developed the disease spontaneously after 8-12 weeks of immunosuppressive corticosteroid treatment and transmit the agent by an airborne route. Definitive antemortem diagnosis of PCP required lung biopsy, which carried significant risk. The efficacy of pentamidine isethionate in the treatment of P. carinii pneumonia was first established in Europe in 1967 and later in the United States. The drug is toxic and has numerous adverse side effects, including severe life-challenging nephrotoxicity. Hence, both diagnosis and treatment of PCP proved hazardous to patients.

P. carinii pneumonia emerged as an important disease when immunosuppressive therapy for cancer first came into general use. The incidence was related to the extent of immunosuppression, and the pneumonitis was invariably fatal if untreated. Based on data from the Centers for Disease Control and Prevention (CDC, then the sole supplier of pentamidine in the U.S.), physicians were most likely to encounter patients with PCP in centers with large programs in cancer chemotherapy or organ transplantation. At SJCRH, where aggressive chemotherapeutic regimens for children with acute lymphocytic leukemia (ALL) were first developed, a successful early diagnostic approach to P. carinii had been instituted, which relied on a high index of suspicion and fastidious care in preventing and treating complications. By 1970, PCP occurred in 20% of patients with ALL, 7% with other malignancies, 40% with severe combined immunodeficiency syndrome, and 4% with organ transplants. At SJCRH, PCP was the most frequent cause of death among children in remission of ALL, impeding the success of curative anticancer therapy.

In 1974, Dr. Hughes demonstrated that the combination of the dihydrofolate reductase inhibitor, trimethoprim (TMP), and the structural analogue of para-aminobenzoic acid, sulfamethoxazole (SMZ), was effective in treating and preventing PCP in cortisone-treated rats. His first pilot studies in humans indicated that orally administered TMP-SMZ was highly effective in patients with mild PCP (80% recovery). In a randomized clinical trial, ~75% of PCP patients receiving either intramuscular pentamidine or oral TMP-SMZ were cured, but with a lack of significant adverse effects in the latter group. Because TMP -SMX had been extensively used for the treatment of bacterial infections with few adverse reactions, the possibility of using the combination for PCP prophylaxis seemed sound. In 1977, Dr. Hughes reported results of a now classic randomized, double-blind, placebo-controlled prophylaxis trial in patients at high risk for PCP. PCP occurred in 20% of those patients given a placebo but in none of those given TMP-SMZ during a two-year period. The US Food and Drug Administration (FDA) soon approved TMP-SMZ for the treatment of PCP, and prophylaxis was widely incorporated in managing high-risk patients. At SJCRH, where 30 to 40 cases of PCP occurred each year, the routine use of TMP-SMZ prophylaxis completely eliminated the disease during the ensuing five years, and only rare sporadic cases were seen over a 20year period, despite ever more intensive anticancer therapy.

In patients with acquired immune deficiency syndrome (AIDS), 50 to 75% of untreated patients will eventually develop PCP. Indeed, the outbreak of AIDS was first heralded by hospital admissions of homosexual men and drug abusers, most of whom presented with PCP and severe T-cell immunodeficiency. An NIH-supported study published in the New England Journal of Medicine in 1981 recommended that “long-term TMP-SMZ prophylaxis should be initiated in such patients after the first episode of pneumocystis.” When Hughes’s prophylaxis was applied in a controlled trial, PCP occurred in 53% of AIDS patients receiving no prophylaxis but in none of those given TMP-SMZ. In 1989, the CDC recommended that all AIDS patients at high risk for PCP should be routinely placed on TMP-SMZ prophylaxis. As a consequence, the incidence of PCP after the diagnosis of HIV infection dropped significantly. CDC analysis of 19,081 AIDS patients at high risk from 1990 to 1999 showed the overall incidence of PCP had decreased to ~5.2%.

In summary, Dr. Hughes’s contributions to healthcare have affected the lives of countless patients worldwide. His was a truly extraordinary series of accomplishments.

Sincerely,

Charles J. Sherr, M.D., Ph.D.

Herrick Foundation Chairman, Department of Tumor Cell Biology Member, National Academies of Sciences and Medicine, and American Academy of Arts & Sciences

March 10, 2023

To the Nominating Committee of the Tennessee Health Care Hall of Fame:

I write to support the nomination of Walter T. Hughes, MD, for consideration into the Tennessee Health Care Hall of Fame. His work in the field of infectious diseases has made an enduring impact on countless lives, from children treated for cancer to patients living with HIV/AIDS. He is among Tennessee’s brightest stars in medicine, and he is richly deserving of this award that honors his tireless work.

Dr. Hughes, a native of Tennessee and graduate of the University of Tennessee College of Medicine, is considered one of the founding fathers of pediatric infectious diseases. His work in Pneumocystis carinii pneumonia (PCP) made him the foremost authority on the disease, including prevention and treatment.

He launched the Infectious Diseases Service at St. Jude Children’s Research Hospital, growing it from a one -person team to a world-renown department. It was at St. Jude where he began to see children who were cured of leukemia die from an opportunistic infection that was triggered by weakened immune systems. The only available treatment at the time was pentamidine isethionate, a particularly toxic treatment. Through animal studies, Dr. Hug hes identified a curative therapy for PCP. Conducting a double-blind, placebo-controlled study, he discovered that combination therapy with trimethoprim and sulfamethoxazole (TMP-SMX) was effective and safe. The results were published in the New England Journal of Medicine and forever changed our prevention strategies and treatment approaches to children with leukemia and PCP.

After he left St. Jude, Dr. Hughes joined the faculty of Johns Hopkins University School of Medicine. It was there that he received a request to discuss a case related to PCP, this time in a young man admitted to the hospital. Dr. Hughes provided his recommendation on treatment and asked for follow-up information on his condition. It later became one of the first published cases of AIDS in the United States. Concerned with the rise of a new, unknown acquired immunodeficiency disorder, Dr. Hughes returned to Tennessee to again lead the Infectious Diseases Departme nt at St. Jude. Much of his work focused on PCP and HIV

He was steadfast in his belief that HIV research was needed, not only for adults but for children. Due to the number of children who acquired HIV through blood transfusions and mother-to-infant transmission, the disease quickly became considered a catastrophic pediatric disease. The National Institutes of Health funded a multimillion -dollar grant that established the pediatric AIDS Clinical Trial Unit, a collaborative effort that included St. Jude, Regional Medical Center and LeBonheur Children’s Hospital. His body of work earned him a nomination for the Lasker Award in 2001.

His influence on the Pediatric Infectious Diseases Society cannot be understated. He served as a founding member and first elected president of the organization. In 1997, he received its Distinguished Physician Award, which was renamed in his honor as the Walter T. Hughes Distinguished Physician Award in 2022. PIDS is now the world’s largest organization of professionals dedicated to the treatment, control and prevention of infectious diseases affecting children.

In his 91 years, Dr. Hughes gave so much to Tennessee and beyond. Entrance into the Tennessee Health Care Hall of Fame would be an incredible recognition for him and his lifelong work a legacy that continues to this day.

Sincerely,

C. Buddy Creech, MD, MPH | Director, Vanderbilt Vaccine Research Program

Edie Carell Johnson Chair and Professor, Pediatric Infectious Diseases Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4) President, Pediatric Infectious Diseases Society Buddy.creech@vumc.org