Robert H. Rubin, M.D.
View Article and Find Full Text PDFXenotransplantation, transplantation into humans of vascularized organs or viable cells from nonhuman species, is a potential solution to shortages of transplantable human organs. Among challenges to application of clinical xenotransplantation are unknown risks of transmission of animal microbes to immunosuppressed recipients or the community. Experience in allotransplantation and in preclinical models suggests that viral infections are the greatest concern.
View Article and Find Full Text PDFXenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance of immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including nonhuman primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission.
View Article and Find Full Text PDFIn this clinicopathological conference, invited experts discussed a previously published case of a patient with nonischemic cardiomyopathy who underwent heart transplantation from a genetically modified pig source animal. His complex course included detection of porcine cytomegalovirus by plasma microbial cell-free DNA and eventual xenograft failure. The objectives of the session included discussion of selection of immunosuppressive regimens and prophylactic antimicrobials for human xenograft recipients, description of infectious disease risk assessment and mitigation in potential xenograft donors and understanding of screening and therapeutic strategies for potential xenograft-related infections.
View Article and Find Full Text PDFXenotransplantation has the potential to address shortages of organs available for clinical transplantation, but concerns exist regarding potential risks posed by porcine microorganisms and parasites (MP) to the health of human recipients. In this study, a risk-based framework was developed, and expert opinion was elicited to evaluate porcine MP based on swine exposure and risk to human health. Experts identified 255 MP to include in the risk assessment.
View Article and Find Full Text PDFIn June 2022, the US Food and Drug Administration Center for Biologics Evaluation and Research held the 73rd meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee for public discussion of regulatory expectations for xenotransplantation products. The members of a joint American Society of Transplant Surgeons/American Society of Transplantation committee on xenotransplantation compiled a meeting summary focusing on 7 topics believed to be key by the committee: (1) preclinical evidence supporting progression to a clinical trial, (2) porcine kidney function, (3) ethical aspects, (4) design of initial clinical trials, (5) infectious disease issues, (6) industry perspectives, and (7) regulatory oversight.
View Article and Find Full Text PDFPorcine cytomegalovirus (PCMV) is widely distributed in pigs and difficult to detect due to latency. PCMV infection of source pigs was associated with early graft failure after cardiac and renal xenotransplantation into nonhuman primates. Importantly, PCMV infection of the first genetically modified pig heart into a human may have contributed to the reduced survival of the patient.
View Article and Find Full Text PDFThis guidance was developed to summarize current approaches to the potential transmission of swine-derived organisms to xenograft recipients, health care providers, or the public in clinical xenotransplantation. Limited specific data are available on the zoonotic potential of pig pathogens. It is anticipated that the risk of zoonotic infection in xenograft recipients will be determined by organisms present in source animals and relate to the nature and intensity of the immunosuppression used to maintain xenograft function.
View Article and Find Full Text PDFremains an important fungal pathogen in immunocompromised hosts. The environmental reservoir remains unknown. Pneumonia (PJP) results from airborne transmission, including in nosocomial clusters, or with reactivation after an inadequately treated infection.
View Article and Find Full Text PDFObjectives: The inadequate supply of transplantable organs necessitates new approaches to donor screening while avoiding transmission of infections. Donor-derived infections are well described. Multiple changes have occurred in donor management and organ utilization, including increased recognition of and therapies for viral infections, the emergence of multidrug antimicrobial-resistant organisms, and identification of some uncommon viral infections transmitted with allografts to clusters of recipients.
View Article and Find Full Text PDFTranspl Infect Dis
December 2022
Xenotransplantation of organs from swine in immunosuppressed human recipients poses many of the same challenges of allotransplantation relative to the risk for infection, malignancy, or graft rejection in proportion to the degree of immunosuppression and epidemiologic exposures. The unique features of xenotransplantation from pigs relative to infectious risk center on the potential for unusual organisms derived from swine causing productive infection, "xenosis" or "xenozoonosis," in the host. Based on experience in allotransplantation, the greatest hazard is due to viruses, due to the relative lack of information regarding the behavior of these potential pathogens in humans, the absence of validated serologic and molecular assays for swine-derived pathogens, and uncertainty regarding the efficacy of therapeutic agents for these organisms.
View Article and Find Full Text PDFMeasures of vaccine-specific antibodies to SARS-CoV-2, as discussed by Werbel and Segev (Page 1316), may ignore responses to contemporaneous variants of concern and relevant cellular immune responses, thereby failing to provide the insights required to optimize clinical care.
View Article and Find Full Text PDFThe increasing global prevalence of SARS-CoV-2 and the resulting COVID-19 disease pandemic pose significant concerns for clinical management of solid organ transplant recipients (SOTR). Wearable devices that can measure physiologic changes in biometrics including heart rate, heart rate variability, body temperature, respiratory, activity (such as steps taken per day) and sleep patterns, and blood oxygen saturation show utility for the early detection of infection before clinical presentation of symptoms. Recent algorithms developed using preliminary wearable datasets show that SARS-CoV-2 is detectable before clinical symptoms in >80% of adults.
View Article and Find Full Text PDFAm J Transplant
December 2020
In regions of high COVID-19 endemicity, the incidence of other respiratory viral illnesses is depressed, which may reflect biologic displacement of other pathogens or the impact of preventive strategies to reduce transmission of SARS-CoV-2.
View Article and Find Full Text PDFBackground: There is a limited understanding of the impact of coronavirus disease 2019 (COVID-19) on the Latinx population. We hypothesized that Latinx patients would be more likely to be hospitalized and admitted to the intensive care unit (ICU) than White patients.
Methods: We analyzed all patients with COVID-19 in 12 Massachusetts hospitals between February 1 and April 14, 2020.
Consistent survival of life-supporting pig heart xenograft recipients beyond 90 days was recently reported using genetically modified pigs and a clinically applicable drug treatment regimen. If this remarkable achievement proves reproducible, published benchmarks for clinical translation of cardiac xenografts appear to be within reach. Key mechanistic insights are summarized here that informed recent pig design and therapeutic choices, which together appear likely to enable early clinical translation.
View Article and Find Full Text PDFSuccessful solid organ transplantation reflects meticulous attention to the details of immunosuppression, balancing risks for graft rejection against risks for infection. The "net state of immune suppression" is a conceptual framework of all factors contributing to infectious risk. Assays that measure immune function in the immunosuppressed transplant recipient relative to infectious risk and allograft function are lacking.
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