Marboe, Charles C.

Abstract Background Characterization of transplant transmitted infections associated with drowned organ donors and the recipients is not well delineated, posing challenges for optimal management and prophylaxis strategies. Broader organ sharing may pose additional considerations due to pathogen variation. Methods We reviewed 22 potential donor disease transmission events (PDDTEs) from drowned donors reported to the Organ Procurement and Transplantation Network (OPTN) ad hoc Disease Transmission Advisory Committee (DTAC) from 2017-2022 to estimate the incidence of PDDTEs among all US drowned organ donors and identify the most common pathogens in this setting. We also characterized donor/recipient epidemiology, infection timing and risk factors, and recipient survival. Results From 2017-2022, drowning was the mechanism of death in 777/74,232 (1.0%) of all US organ donors, from whom 2500 organs were transplanted. Among the 22 PDDTEs, there were 70 organ recipients. The median donor age was 17.5 years (range 1-70 years) and lung recipients accounted for 5/70 organ recipients. All PDDTE reports were submitted due to recipient disease, and index cases occurred 2-19 days post-transplant. 7/22 (7/777 drowned donors, 0.9%) PDDTEs were associated with pathogens consistent with plausible waterborne transmission, of which 4 were due to invasive molds (Zygomycetes and Scedosporium) and 3 were due to bacteria (Pseudomonas and Legionella). Of the 21 organ recipients from these 7 donors, 8 had proven or probable infections. 6/8 recipients had severe infection with 3 deaths, all from invasive mold infections. There were no identifiable infection risk factors related to drowning water source, donor immersion time, or geographic region. However, donor/recipient regional discordance occurred in 5/21 recipients, demonstrating the trend in broader organ sharing. Conclusion Though rare, organ recipients are at risk for transplant transmitted infection from drowned donors, particularly invasive mold infections. All infections occurred within the first month after transplant with high associated mortality. Though optimal management and prophylaxis strategies in these scenarios remain uncertain, post-transplant vigilance for early infection is paramount. Disclosures Helen S. Te, MD, CVS Caremark: Advisor/Consultant Lara A. Danziger-Isakov, MD, MPH, Aicuris: clinical research contract, paid to institutio|Ansun BioPharma: clinical research contract, paid to institution|Astellas: Advisor/Consultant|Astellas: clinical research contract, paid to institutio|Merck: clinical research contract, paid to institutio|Pfizer: Grant/Research Support|Takeda: clinical research contract, paid to institutio Anil J. Trindade, MD, CareDx, Inc.: Advisor/Consultant|CareDx, Inc.: Grant/Research Support|TFF Pharmaceuticals: Advisor/Consultant|Veloxis Pharmaceuticals, Inc.: Grant/Research Support

ABSTRACTBackgroundCoccidioidomycosis is a fungal infection that poses a serious risk when transmitted through organ transplantation. We analyzed cases reported to the Organ Procurement and Transplantation Network ad hoc Disease Transmission Advisory Committee from 2013 to 2022.MethodsDonors and/or recipients who had positive Coccidioides immitis/posadasii serology, pathology, and/or culture were included in this study. Cases adjudicated as ‘proven’ or ‘probable’ were analyzed for donor infection risk factors, the timing of infection, transmission by organ type, clinical manifestations, and recipient outcomes. Patient and facility identifiers were removed prior to review.ResultsDuring this time period, 73 potential instances of Coccidioides donor disease transmission events were reported. Among them, infection was transmitted from seven deceased donors to eight recipients. All seven deceased donors had prior infection or exposure to regions where coccidioidomycosis is endemic. Of 20 individuals receiving organs from these donors, eight developed infection, resulting in a 40% transmission rate. The median time to diagnosis post‐transplant was 39 days. Disseminated disease occurred in six recipients, five of whom died from the infection. Notably, none of the recipients who received prophylactic antifungal treatment died from the infection.ConclusionDespite its rarity, donor‐derived Coccidioides infection is a serious concern, particularly due to the high mortality rate in the early post‐transplant period. To mitigate these risks, a thorough assessment of donor exposure history, coupled with donor serology and bronchoalveolar lavage cultures, can effectively guide post‐transplant antifungal prophylaxis. Prompt reporting is crucial to prevent Coccidioides infections among other recipients. image

AbstractBackgroundBetter access to direct‐acting antiviral (DAA) therapy has broadened the utilization of hepatitis C virus (HCV) nucleic acid testing (NAT) positive organs with excellent outcomes. However, DAA therapy has been associated with hepatitis B virus (HBV) reactivation.AimTo determine the risk of HBV transmission or reactivation with utilization of HBV core antibody positive (HBcAb+) and HCV NAT positive (HCV+) organs, which presumably required DAA therapy.MethodsThe number of HBcAb+ donors with delineated HCV NAT status was obtained from the Organ Procurement and Transplantation Network (OPTN) database. The number of unexpected HBV infections from transplanted organs adjudicated as “proven” or “probable” transmission was obtained from the OPTN Ad Hoc Disease Transmission Advisory Committee database. A chart review of the donors of “proven” or “probable” cases was conducted.ResultsFrom January 1, 2016, to December 31, 2021, 7735 organs were procured from 3767 HBcAb+ donors and transplanted into 7469 recipients; 545 (14.5%) donors were also HCV+. HBV transmission or reactivation occurred in seven recipients. The rate is not significantly different between recipients of HCV+ (0.18%, 2/1115) and the HCV NAT negative (HCV‐) organs (0.08%, 5/6354) (p = 0.28) or between recipients of HCV+ and HCV‐ livers as well as non‐liver organs. HBV transmission or reactivation occurred within a median of 319 (range, 41–1117) days post‐transplant in the setting of missing, inadequate, or truncated prophylaxis.ConclusionHBV reactivation associated with DAA therapy for HBcAb+ HCV+ organs is less frequent than reported in the non‐transplant population, possibly due to the common use of HBV prophylaxis in the at‐risk transplant population. image

AbstractBackgroundDecisions to transplant organs from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) nucleic acid test‐positive (NAT+) donors must balance risk of donor‐derived transmission events (DDTE) with the scarcity of available organs.MethodsOrgan Procurement and Transplantation Network (OPTN) data were used to compare organ utilization and recipient outcomes between SARS‐CoV‐2 NAT+ and NAT– donors. NAT+ was defined by either a positive upper or lower respiratory tract (LRT) sample within 21 days of procurement. Potential DDTE were adjudicated by OPTN Disease Transmission Advisory Committee.ResultsFrom May 27, 2021 (date of OTPN policy for required LRT testing of lung donors) to January 31, 2022, organs were recovered from 617 NAT+ donors from all OPTN regions and 53 of 57 (93%) organ procurement organizations. NAT+ donors were younger and had higher organ quality scores for kidney and liver. Organ utilization was lower for NAT+ donors compared to NAT– donors. A total of 1241 organs (776 kidneys, 316 livers, 106 hearts, 22 lungs, and 21 other) were transplanted from 514 NAT+ donors compared to 21 946 organs from 8853 NAT– donors. Medical urgency was lower for recipients of NAT+ liver and heart transplants. The median waitlist time was longer for liver recipients of NAT+ donors. The match run sequence number for final acceptor was higher for NAT+ donors for all organ types. Outcomes for hospital length of stay, 30‐day mortality, and 30‐day graft loss were similar for all organ types. No SARS‐CoV‐2 DDTE occurred in this interval.ConclusionsTransplantation of SARS‐CoV‐2 NAT+ donor organs appears safe for short‐term outcomes of death and graft loss and ameliorates the organ shortage. Further study is required to assure comparable longer term outcomes. image

Abstract Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance‐based variant filtering. PPP1R13L encodes inhibitor of apoptosis‐stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months‐9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene‐disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel‐based genetic testing for paediatric DCM.