The June 24, 2021 Medical Grand Rounds featured presentations by both the 2020 and 2021 Iva Dostanic, MD, PhD, Physician-Scientist Trainee Award winners Rupak Datta, MD/PhD, MPH, instructor (infectious diseases); and Ana Luisa Perdigoto, MD, PhD, instructor (endocrinology).
Peter Aronson, MD, C.N.H. Long Professor of Medicine (Nephrology) and professor of cellular and molecular physiology, introduced the lecture. “This is a special medical grand rounds in which we celebrate the life and legacy of Iva Dostanic, who came to Yale as a member of our residency program. Today marks the tenth time we are presenting the award in Iva’s name to an outstanding physician-scientist trainee in our department. The first recipient was Iva herself who received the award in the 2011-2012 academic year,” he said.
“Iva’s parents have become devoted friends of Yale and we are very grateful that they established an endowed fund in Iva’s name to support physician-scientist career development in our department. Due to their generous donations, the endowment has grown very rapidly and will provide support for future generations of physician-scientists in the Yale Department of Medicine,” continued Aronson.
In his presentation, Datta, the 2020 award winner, discussed “Antibiotic Stewardship to Promote Palliative Care in Older Adults Near the End of Life.” He started his lecture by sharing the real world case of a 72-year-old woman with metastatic non-small cell lung cancer who had bacteremia. He explained that the best course of treatment was antibiotic stewardship and palliative care.
Datta explained that “much of the literature on antibiotic use during end-of-life care is focused on two key populations: older adults with advanced cancer and older adults with advanced dementia.” In patients with advanced cancer, antibiotic exposure is common due to the possible high risks of infection in this population due to a variety of patient associated and treatment associated factors. In those patients with advanced dementia, comfort is a goal of care, but antimicrobial use is extensive.
He cited numerous studies that show strong evidence that antibiotic use during end of life care may cause harm. “Antibiotic resistance is one of the greatest health threats of the 21st century,” said Datta
“There is little evidence of benefit,” he said. The potential of prolonged survival and relief of symptoms may motivate physicians to prescribe antibiotics, but no trials have been conducted to determine outcomes in terminally ill patients and there is a lack of guidance from professional societies.
Datta discussed the 2019 publication, “Perspectives on Antimicrobial Use at the End of Life among Antibiotic Stewardship Programs: A Survey of the Society for Healthcare Epidemiology of America Research Network” which described a survey of antibiotic stewardship programs. They found that among the 36 hospitals that responded, 92% had a palliative care service but only 9% of them had formal collaborations between palliative care and antimicrobial stewardship programs. In addition, approval of antibiotics appeared to vary across facilities according to patient goals of care.
Through this work, Datta and team proposed a framework ‘through which antibiotic stewardship may promote palliative care.’ In his 2017 “Burden and Management of Multidrug-Resistant Organisms in Palliative Care” publication, the authors acknowledged the challenge of infections during palliative care and urged further research into infections due to multidrug-resistant organisms in these settings. Datta circled back to the patient, who was treated with oritavancin for the infection symptoms, remained fever-free, and died in hospice care two weeks later.
Through his current research, Datta hopes to bring attention to and evaluate the ‘important and understudied population’ of homebound older adults and evaluate antibiotic prescribing through the VA Home-Based Primary Care Program. His multidisciplinary team will look at national data from veterans receiving home-based primary care, and may ‘offer one potential platform to promote antibiotic stewardship,’ he said.
Datta’s research is supported by the NIA IMPACT Collaboratory CDA; NIA IMPACT Collaboratory Pilot Grant; Yale Physician-Scientist Development Award; and the Yale Pepper Center REC Small Grant Award. Datta won the Dostanic Award in 2020, but his lecture was delayed due to the COVID-19 pandemic.
The second speaker was Ana Luisa Perdigoto, MD, PhD, instructor (endocrinology), the 2021 Iva Dostanic Award winner, who discussed her research in, “Clinical and Preclinical Insights into the Mechanisms of Checkpoint Inhibitor-induced Diabetes.”
Perdigoto began her talk by reviewing the immunological equilibrium. On the activation end, effector T cells and stimulatory ligands (e.g. CD28) ‘play an important role in reactions again pathogens,’ but when uncontrolled, can cause inflammatory diseases. The opposite side is tolerance, where regulatory T cells and inhibitory ligands, such as CTLA-4 and PD-1, are important for controlled responses to pathogens and avoiding responses to self. Immunotherapies that target inhibitory molecules, such as CTLA-4, PD-1, and PD-L1, have revolutionized cancer therapy but have led to immune-related adverse events, with one of the most common being endocrinopathies.
Perdigoto’s research focuses on checkpoint inhibitor-induced diabetes (CPI-DM), which has ‘no definitive criteria for this emerging form of diabetes, but we typically describe it as new onset hyperglycemia requiring insulin treatment and evidence of insulin deficiency in patients following checkpoint inhibitor treatment (CPI),” explained Perdigoto. Incidents of CPI-DM are caused primarily with anti-PD-1 or anti-PD-L1 and has occurred between five days to 228 weeks after treatment.
In 2019 paper in The Lancet Diabetes & Endocrinology, the team found that progression to hyperglycemia and beta cell loss occurs rapidly in these patients. In addition, some patients present with elevated pancreatic enzymes and evidence of pancreatic inflammation. Curious about the effects on human beta cells, the researchers performed single cell RNA sequencing, and found that cells that were exposed to interferon-gamma were potentially more susceptible to killing by immune cells. To further understand the connection, they tested their hypothesis in mice models, which mirrored their clinical experience. Through their mouse models, they were able to identify pathways in islet and immune cells that were activated after anti-PD-L1 treatment that could explain the development of CPI-DM. To understand the beta cell responses, the team accessed differentially expressed genes and found differences in genes involved in various pathways. They partnered with medical oncology to determine if there was a benefit to blocking TNFa in an CPI-DM afflicted patient using infliximab. The patient retained beta cell function and was able to stop using insulin due to improved glucose control.
Perdigoto’s work has been supported by the K12 Calabresi Immuno-Oncology Training Program; JDRF Advanced Postdoctoral Fellowship Award; Endocrine Fellows Foundation Grant; T32 Grant (Endocrinology Section); NCI R01; NIAID R21; and Helmsley/Parker Institute.
Datta and Perdigoto are the ninth and tenth recipients of this prestigious award respectively. Aronson spoke about the creation of the award in Dostanic’s honor. “She [Iva] brought passion, energy, elegance, playfulness, humor, and joy to all aspects of her life. Even during the last phase of her illness, Iva dismissed her physical ailments and her face literally glowed with joy describing her exciting research ideas. Iva’s passion and love for science and medicine despite the most adverse circumstances possible were awe inspiring. Iva’s passion, commitment and optimism despite all odds represented the very ideal of what it means to be a physician-scientist.”
“To students and trainees in the audience, we wish to emphasize that in creating this award, we do not ask you to strive to be another Iva Dostanic, as Iva’s accomplishments even before starting her residency were uniquely exceptional. She was a true force of nature. What we do hope is that you will be inspired by Iva’s love of science and medicine, and especially by the enormous joy she found in her work right up until her last days. And we hope that imbued with Iva’s spirit, you each will also find joy and fulfillment as you apply your own special gifts and talents to advance the science or practice or teaching of medicine,” said Aronson.
Due to COVID-19 restrictions, Iva’s parents, Dragana and Predrag, watched the presentations virtually. Those with a Yale ID can watch the presentations on the website.
The Department of Internal Medicine at Yale is among the nation's premier departments, bringing together an elite cadre of clinicians, investigators and educators in one of the world's top medical schools. To learn more, visit Internal Medicine.