Solid Organ Transplantation From Hepatitis B Virus–Positive Donors: Consensus Guidelines for Recipient Management

Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non‐liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti‐HBc+) donors. Organs from anti‐HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non‐liver recipients but is not recommended in immune non‐liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost‐effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.     

Organ transplantation from “increased infectious risk donors”: the experience of the Nord Italia Transplant program — A retrospective study

The purpose of this study was to assess the safety and the clinical outcome associated with organ transplantation from increased infectious risk donors (IRD). We retrospectively identified all adult deceased IRD referred to the Nord Italia Transplant program coordinating center from November 2006 to November 2011. All potential donors were screened for social risk factors that may increase the risk of donor‐derived infection with human immunodeficiency (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). All recipients were followed monthly for the first 6 months post‐transplant. A total of 86 potential IRD were identified during the study period. Three hundred and seventy‐nine organs from IRD were offered to the transplant centers, but only 185 (48.8%) were used for transplantation. Organs from IRD were transplanted into 174 recipients. The complete follow‐up data were available for 152 of 174 (87.3%) recipients. During a mean follow‐up of 11.7 months (median 12; range 2.4–12), no transmission of HIV, HBV, or syphilis was documented by serology and nucleic acid testing (NAT) testing. Two patients transplanted with organs from HCV‐RNA‐positive donors, as expected, developed post‐transplant HCV infection. In conclusion, the use of organs from IRD was associated with a safe increase in the transplant procedures in our country.     

Screening for Zika virus in deceased organ donors in Florida

Zika virus (ZIKV) cases have been detected across the United States (US) and locally acquired cases have been reported in Florida. Currently, there are no ZIKV screening guidelines and no data on the incidence among organ donors in the US. This retrospective study was conducted at Jackson Memorial‐Miami Transplant Institute. Positive ZIKV tests in local deceased organ donors were investigated from 6/2016 to 1/2017. We evaluated demographics and risk factors for ZIKV infection among organ donors and transplant outcomes among recipients of donors with positive ZIKV testing. One hundred forty‐two donors were analyzed. Ten percent had traveled to ZIKV‐endemic countries and 19% had outdoor occupations. Only 3% had positive ZIKV IGG. None had a positive ZIKV IGM or PCR. ZIKV‐positive donors were more likely to have traveled to ZIKV‐endemic countries (50% vs. 9%, P = .05). The kidneys from a ZIKV‐positive donor were transplanted in our hospital with no 6‐month rejection, graft failure, or death in the recipients. Our study demonstrated a low prevalence of ZIKV among deceased donors in our community. Despite local ZIKV transmission, ZIKV was more common in donors who traveled to ZIKV‐endemic countries. This cohort demonstrated excellent outcomes in recipients of ZIKV IGG‐positive donors. However, larger studies are needed.     

Early emergence of anti‐HCV antibody implicates donor origin in recipients of an HCV‐infected organ

Hepatitis C virus (HCV) seroconversion among HCV‐uninfected transplant recipients from HCV‐infected (NAT+/Antibody+) or HCV‐exposed (NAT?/Antibody+) donors has been reported. However, the origin of anti‐HCV antibody and the implications of seroconversion remain unknown. We longitudinally tested plasma from HCV‐uninfected kidney (n = 31) or heart transplant recipients (n = 9) of an HCV NAT+ organ for anti‐HCV antibody (both IgG and IgM isotypes). Almost half of all participants had detectable anti‐HCV antibody at any point during follow‐up. The majority of antibody‐positive individuals became positive within 1‐3 days of transplantation, and 6 recipients had detectable antibody on the first day posttransplant. Notably, all anti‐HCV antibody was IgG, even in samples collected posttransplant day 1. Late seroconversion was uncommon (≈20%‐25% of antibody+ recipients). Early antibody persisted over 30 days in kidney recipients, whereas early antibody dropped below detection in 50% of heart recipients within 2 weeks after transplant. Anti‐HCV antibody is common in HCV‐uninfected recipients of an HCV NAT+ organ. The IgG isotype of this antibody and the kinetics of its appearance and durability suggest that anti‐HCV antibody is donor derived and is likely produced by a cellular source. Our data suggest that transfer of donor humoral immunity to a recipient may be much more common than previously appreciated.     

Transplantation of hepatitis C virus (HCV) antibody positive,nucleic acid test negative donor kidneys to HCV negative patients frequently results in seroconversion but not HCV viremia

Anecdotal reports have suggested that transplantation of hepatitis C virus (HCV) antibody positive (Ab+)/nucleic acid test negative (NAT?) donor kidneys into HCV negative recipients is not associated with HCV transmission. We reviewed our center's outcomes of 32 HCV negative patients who received kidney allografts from 25 donors who were HCV Ab+/NAT?. The mean recipient age was 56.9 ± 12.1 years and the mean donor age was 41.5 ± 14 years, with a median Kidney Donor Profile Index (KDPI) of 68%. Twelve donors (48%) met Public Health Service (PHS) increased risk status. All patients received antithymocyte globulin induction followed by tacrolimus, mycophenolate mofetil, and steroid maintenance immunosuppression. With a mean follow‐up posttransplant of 10 ± 2.7 months, 1‐ and 3‐ month serum creatinine levels were 1.7 ± 0.8 and 1.3 ± 0.4, respectively, and patient and graft survival rates were 100% and 97%, respectively. Fourteen patients (44%) seroconverted and became HCV Ab+ posttransplant. However, all 32 patients were HCV RNA negative at 1‐ and 3‐ months posttransplant, and 27 and 8 patients tested at 6‐ and 12‐months posttransplant, respectively, remain HCV RNA negative. In conclusion, transplantation of HCV Ab+/NAT? kidneys to HCV negative recipients frequently causes HCV Ab seroconversion but not HCV viremia.     

Transplant Infectious Diseases: A Review of the Scientific Registry of Transplant Recipients Published Data

The Scientific Registry of Transplant Recipients (SRTR) serves to collect data on organ transplants performed in the United States. Although the infectious diseases data are limited and include mostly pretransplant serologies and other nonspecific infection‐related outcomes, this multicenter data collection allows for insightful national data and the ability to monitor trends over time. We reviewed the published concise reports for each organ type in SRTR reports containing data from 2005 to 2014, and summarized our findings with respect to cytomegalovirus (CMV), Epstein‐Barr virus, posttransplant lymphoproliferative disorder (PTLD), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, general infection, and prophylaxis. Our review highlights a few developments. While rates of donor–recipient CMV serology combinations remain fairly constant over time, there are generally more seronegative donors and recipients among living donor transplants. There has been a reduction in PTLD for pediatric transplant recipients. There has also been a slight reduction in anti‐HBV core antibody–positive donor organs and stable reporting of HCV‐positive donor organs and HIV‐positive recipients.     

Quantifying the risk of undetected HIV,hepatitis B virus,or hepatitis C virus infection in Public Health Service increased risk donors

To reduce the risk of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) transmission through organ transplantation, donors are universally screened for these infections by nucleic acid tests (NAT). Deceased organ donors are classified as “increased risk” if they engaged in specific behaviors during the 12 months before death. We developed a model to estimate the risk of undetected infection for HIV, HBV, and HCV among NAT‐negative donors specific to the type and timing of donors’ potential risk behavior to guide revisions to the 12‐month timeline. Model parameters were estimated, including risk of disease acquisition for increased risk groups, number of virions that multiply to establish infection, virus doubling time, and limit of detection by NAT. Monte Carlo simulation was performed. The risk of undetected infection was <1/1 000 000 for HIV after 14 days, for HBV after 35 days, and for HCV after 7 days from the time of most recent potential exposure to the day of a negative NAT. The period during which reported donor risk behaviors result in an “increased risk” designation can be safely shortened.     

Liver allografts from hepatitis C positive donors can offer good outcomes in hepatitis C positive recipients: a US National Transplant Registry analysis

Organ donors are screened for the hepatitis C antibody (anti‐HCV) and those with positive tests can be used under extended criteria donation. However, there is still a question of long‐term organ viability. The aim of this study was to assess the long‐term outcomes of anti‐HCV positive (HCV+) liver grafts. The US Organ Procurement and Transplantation Network Scientific Registry was reviewed for the period from April 1994 to February 6, 2008 and 56 275 liver transplantations were analyzed. In total, there were 19 496 HCV+ recipients and 934 HCV+ donors. Patient and graft survival were assessed accounting for both donor and recipient anti‐HCV status. Multivariable proportional hazards survival models were developed to adjust for factors known to affect post‐transplant survival. With anti‐HCV negative (HCV?) recipient/HCV? donor as the reference, the adjusted hazard ratio for death was similar for HCV+ recipient/HCV? donor compared with HCV+ recipient/HCV+ donor (1.176 vs. 1.165, P = 0.91). Our results suggest that HCV+ liver donors do not subject the HCV+ recipient to an increased risk for death over the HCV? donor, keeping in mind that careful donor and recipient selection is critical for the proper use of these extended criteria donors.     

The Outcomes of Kidney Transplantation in Hepatitis B Surface Antigen (HBsAg)–Negative Recipients Receiving Graft From HBsAg‐Positive Donors: A Retrospective,Propensity Score‐Matched Study

The outcomes of kidney transplantation (KT) from hepatitis B surface antigen–positive [HBsAg(+)] donors to HBsAg(?) recipients remain inconclusive, possibly due to substantial differences in methodological and statistical models, number of patients, follow‐up duration, hepatitis B virus (HBV) prophylactic regimens and hepatitis B surface antibody (anti‐HBs) levels. The present retrospective, longitudinal study ( clinicaltrial.gov NCT02044588) using propensity score matching technique was conducted to compare outcomes of KT between HBsAg(?) recipients with anti‐HBs titer above 100 mIU/mL undergoing KT from HBsAg(+) donors (n = 43) and HBsAg(?) donors (n = 86). During the median follow‐up duration of 58.2 months (range 16.7–158.3 months), there were no significant differences in graft and patient survivals. No HBV‐infective markers, including HBsAg, hepatitis B core antibody, hepatitis B extracellular antigen and HBV DNA quantitative test were detected in HBsAg(+) donor group. Renal pathology outcomes revealed comparable incidences of kidney allograft rejection while there were no incidences of HBV‐associated glomerulonephritis and viral antigen staining. Recipients undergoing KT from HBsAg(+) donors with no HBV prophylaxis (n = 20) provided comparable outcomes with those treated with lamivudine alone (n = 21) or lamivudine in combination with HBV immunoglobulin (n = 2). In conclusion, KT without HBV prophylaxis from HBsAg(+) donors without hepatitis B viremia to HBsAg(?) recipients with anti‐HBs titer above 100 mIU/mL provides excellent graft and patient survivals without evidence of HBV transmission.

     

Impact of the OPTN transmissible diseases policy and US PHS increased risk donor guidelines on living donor candidates

Donor‐derived human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) transmissions in transplantation have led to policies mandating assessment of donor behavioral history, and disclosure of donor increased risk (IR) status to recipients. Organ Procurement Transplantation Network (OPTN) policy safeguards were promulgated in the context of deceased donation, with its narrow time window for organ utilization and uncertainty about donor history. These policies have been applied to living donation without substantive data on risk of disease transmission in living donor transplantation. Unlike for deceased donors, the OPTN does not collect data on living donor IR status. Given the feasibility of thorough living donor evaluation via already‐mandated lab tests and clinical assessments, living donor IR assessment and associated disclosures may have limited benefit in improving recipient informed consent. Applying the current IR policy to living donors may also introduce unintended consequences to donors and recipients, causing donors psychological harm, delays in donation to avoid IR status disclosure, and potential withdrawal from donation. We suggest strategies that reduce risk of harm to donor candidates while maintaining policy compliance, and review additional approaches for evaluating risk of disease transmission in living donor candidates. Data on the risk of disease transmission by living donors are needed to inform policy modification.     

Impact of US Public Health Service increased risk deceased donor designation on organ utilization

Under US Public Health Service guidelines, organ donors with risk factors for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) are categorized as increased risk donors (IRD). Previous studies have suggested that IRD organs are utilized at lower rates than organs from standard risk donors (SRD), but these studies were conducted prior to universal donor nucleic acid test screening. We conducted risk‐adjusted analyses to determine the effect of IRD designation on organ utilization using 2010‐2017 data (21 626 heart, 101 160 kidney, 52 714 liver, and 16 219 lung recipients in the United States) from the Organ Procurement and Transplantation Network. There was no significant difference (P < .05) between risk‐adjusted utilization rates for IRD vs SRD organs for adult hearts and livers and pediatric kidneys, livers, and lungs. Significantly lower utilization was found among IRD adult kidneys, lungs, and pediatric hearts. Analysis of the proportion of transplanted organs recovered from IRD by facility suggests that a subset of facilities contribute to the underutilization of adult IRD kidneys. Along with revised criteria and nomenclature to identify donors with HIV, HBV, or HCV risk factors, educational efforts to standardize informed consent discussions might improve organ utilization.     

Successful Lung Transplantation From Hepatitis C Positive Donor to Seronegative Recipient

Lung transplantation using RNA+ hepatitis C (HCV+) donors to seronegative recipients is not currently performed due to the very high risk of transmission. Previous reports have shown poor survival when this practice was applied. The emergence of new direct‐acting antiviral drugs (DAA) suggests a high chance of sustained virologic response in immunocompetent patients. We report here successful transplantation of lungs from HCV+ donor to HCV? recipient. The recipient was an HCV? patient with chronic lung allograft dysfunction. Viral transmission occurred early posttransplant but excellent clinical outcomes were observed including elimination of HCV after 12 weeks of treatment using DAAs.     

Donor‐Derived Strongyloides stercoralis Infection in Solid Organ Transplant Recipients in the United States, 2009–2013

Infection with Strongyloides stercoralis is typically asymptomatic in immunocompetent hosts, despite chronic infection. In contrast, immunocompromised hosts such as solid organ transplant recipients are at risk for hyperinfection syndrome and/or disseminated disease, frequently resulting in fatal outcomes. Infection in these recipients may result from reactivation of latent infection or infection through transmission from an infected donor. We describe the Centers for Disease Control and Prevention's experience with seven clusters of donor‐derived infection from 2009 to 2013. Six of the seven (86%) donors were born in Latin America; donor screening was not performed prior to organ transplantation in any of these investigations. Eleven of the 20 (55%) organ recipients were symptomatic, two of whom died from complications of strongyloidiasis. We also describe the New York Organ Donor Network (NYODN) experience with targeted donor screening from 2010 to 2013. Of the 233 consented potential donors tested, 10 tested positive for Strongyloides antibody; and 18 organs were transplanted. The majority (86%) of the donors were born in Central or South America. Fourteen recipients received prophylaxis after transplantation; no recipients developed strongyloidiasis. The NYODN experience provides evidence that when targeted donor screening is performed prior to transplantation, donor‐derived infection can be averted in recipients.     

Donor‐derived infections: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation will review the current state of the art of donor‐derived infections. Specifically, the guideline will summarize standardized definitions and approaches to defining imputability, updated data on the epidemiology of donor‐derived infections, and approaches to risk mitigation against transmission of infections. This update will additionally provide guidance on the use of HIV+ donors in HIV+ recipients, the use of HCV‐viremic donors in non‐viremic recipients, donors with endemic infections, and donors with bacteremia, meningitis, and encephalitis. Lastly, the guidance will summarize an approach to recipients with a suspected donor‐derived infection.     

Coccidioidomycosis Transmission Through Organ Transplantation: A Report of the OPTN Ad Hoc Disease Transmission Advisory Committee

Donor‐derived coccidioidomycosis has caused unexpected morbidity and mortality in transplant recipients. All proven or probable reports of donor‐derived coccidioidomycosis to the Disease Transmission Advisory Committee between 2005 and August 2012 were reviewed. Six reports of proven or probable coccidioidomycosis were discovered. In four of six, the infection was first detected at autopsy in the recipient. In two cases it was first identified in the donor. Twenty‐one recipients received organs from these six donors. Transmission occurred in 43% at a median of 30 days posttransplant with a mortality rate of 28.5%. Eleven recipients received preemptive antifungals, seven did not receive treatment, and treatment information was not reported for three recipients. Five of seven who did not receive prophylaxis/treatment died and all 11 who received early therapy survived. Six deaths occurred 14 to 55 days after transplant, with a median of 21 days. For exposed recipients, donor‐derived coccidioidomycosis is a significant cause of morbidity and mortality. Evidence of infection in one recipient should prompt immediate evaluation for treatment of all other recipients from the same donor as preemptive treatment was effective. Further studies are needed to decide whether all donors from endemic areas should have routine serologic screening.     

Use of HCV Ab+/NAT− donors in HCV naïve renal transplant recipients to expand the kidney donor pool

Hepatitis C (HCV) disease transmission from the use of HCV antibody‐positive and HCV nucleic acid test‐negative (HCV Ab+/NAT?) kidneys have been anecdotally reported to be absent. We prospectively analyzed kidney transplant (KT) outcomes from HCV Ab+/NAT? donors to HCV naïve recipients under T‐cell depleting early steroid withdrawal immunosuppression. Allografts from 40 HCV Ab+/NAT? donors were transplanted to 52 HCV Ab? recipients between July 2016 and February 2018. Thirty‐three (82.5%) of donors met Public Health Service (PHS) increased risk criteria. De novo HCV infection was detected at 3 months post‐KT in one recipient (1.9%). This was a case of transmission from a HCV Ab+ NAT+ donor with an initial false‐negative NAT completed using sample collected on donor hospital admission (day 2). At the time of HCV diagnosis, a stored donor sample collected during procurement (day 4) was tested and resulted NAT‐positive. Subsequently, sustained virologic response (SVR) was achieved with 12 weeks of glecaprevir/pibrentasvir. One death with functioning graft at 261 days post‐KT was determined not related to HCV or donor factors. This experience provides evidence of a low transmission rate of HCV from HCV Ab+/ NAT? kidney donors, thereby arguing for increasing utilization.     

Donor-derived human herpesvirus 8 and development of Kaposi sarcoma among 6 recipients of organs from donors with high-risk sexual and substance use behavior

Kaposi sarcoma (KS) can develop following organ transplantation through reactivation of recipient human herpesvirus 8 (HHV-8) infection or through donor-derived HHV-8 transmission. We describe 6 cases of donor-derived HHV-8 infection and KS investigated from July 2018 to January 2020. Organs from 6 donors, retrospectively identified as HHV-8-positive, with a history of drug use disorder, were transplanted into 22 recipients. Four of 6 donors had risk factors for HHV-8 infection reported in donor history questionnaires. Fourteen of 22 organ recipients (64%) had evidence of posttransplant HHV-8 infection. Lung recipients were particularly susceptible to KS. Four of the 6 recipients who developed KS died from KS or associated complications. The US opioid crisis has resulted in an increasing number and proportion of organ donors with substance use disorder, and particularly injection drug use history, which may increase the risk of HHV-8 transmission to recipients. Better awareness of the risk of posttransplant KS for recipients of organs from donors with HHV-8 infection risk could be useful for recipient management. Testing donors and recipients for HHV-8 is currently challenging with no validated commercial serology kits available. Limited HHV-8 antibody testing is available through some US reference laboratories and the Centers for Disease Control and Prevention.     

Changes in Utilization and Discard of Hepatitis C–Infected Donor Livers in the Recent Era

The impact of interferon (IFN)‐free direct‐acting antiviral (DAA) hepatitis C virus (HCV) treatments on utilization and outcomes associated with HCV‐positive deceased donor liver transplantation (DDLT) is largely unknown. Using the Scientific Registry of Transplant Recipients, we identified 25 566 HCV‐positive DDLT recipients from 2005 to 2015 and compared practices according to the introduction of DAA therapies using modified Poisson regression. The proportion of HCV‐positive recipients who received HCV‐positive livers increased from 6.9% in 2010 to 16.9% in 2015. HCV‐positive recipients were 61% more likely to receive an HCV‐positive liver after 2010 (early DAA/IFN era) (aRR:_1.451.61_1.79, p < 0.001) and almost three times more likely to receive one after 2013 (IFN‐free DAA era) (aRR:_2.582.85_3.16, p < 0.001). Compared to HCV‐negative livers, HCV‐positive livers were 3 times more likely to be discarded from 2005 to 2010 (aRR:_2.692.99_3.34, p < 0.001), 2.2 times more likely after 2010 (aRR:_1.802.16_2.58, p < 0.001) and 1.7 times more likely after 2013 (aRR:_1.371.68_2.04, p < 0.001). Donor HCV status was not associated with increased risk of all‐cause graft loss (p = 0.1), and this did not change over time (p = 0.8). Use of HCV‐positive livers has increased dramatically, coinciding with the advent of DAAs. However, the discard rate remains nearly double that of HCV‐negative livers. Further optimization of HCV‐positive liver utilization is necessary to improve access for all candidates.     

Risk factors for multidrug‐resistant organisms among deceased organ donors

Donor infection or colonization with a multidrug‐resistant organism (MDRO) affects organ utilization and recipient antibiotic management. Approaches to identifying donors at risk of carrying MDROs are unknown. We sought to determine the risk factors for MDROs among transplant donors. A multicenter retrospective cohort study was conducted at four transplant centers between 2015 and 2016. All deceased donors who donated at least one organ were included. Cultures obtained during the donor's terminal hospitalization and organ procurement were evaluated. The primary outcome was isolation of an MDRO on culture. Multivariable Cox regression was used to determine risk factors associated with time to donor MDRO. Of 440 total donors, 64 (15%) donors grew an MDRO on culture. Predictors of an MDRO on donor culture included hepatitis C viremia (hazard ratio [HR] 4.09, 95% confidence interval [CI] 1.71‐9.78, P = .002), need for dialysis (HR 4.59, 95% CI 1.09‐19.21, P = .037), prior hematopoietic cell transplant (HR 7.57, 95% CI 1.03‐55.75, P = .047), and exposure to antibiotics with a narrow gram‐negative spectrum (HR 1.13, 95% CI 1.00‐1.27, P = .045). This is the first study to determine risk factors for MDROs among deceased donors and will be important for risk stratifying potential donors and informing transplant recipient prophylaxis.     

Transplantation of kidneys from hepatitis C–infected donors to hepatitis C–negative recipients: Single center experience

Our aim was to evaluate the safety of transplanting kidneys from HCV‐infected donors in HCV‐uninfected recipients. Data collected from 53 recipients in a single center, observational study included donor and recipient characteristics, liver and kidney graft function, new infections and de novo donor‐specific antibodies and renal histology. Treatment with a direct‐acting antiviral regimen was initiated when HCV RNA was detected. The mean ± SD age of recipients was 53 ± 11 years, 34% were female, 19% and 79% of recipients were white and African American, respectively. The median and interquartile range (IQR) time between transplant and treatment initiation was 76 (IQR: 68‐88) days. All 53 recipients became viremic (genotype: 1a [N = 34], 1b [N = 1], 2 [N = 3], and 3 [N = 15]). The majority (81%) of recipients did not experience clinically significant increases (>3 times higher than upper limit of the normal value) in aminotransferase levels and their HCV RNA levels were in the 5 to 6 log range. One patient developed fibrosing cholestatic hepatitis with complete resolution. All recipients completed antiviral treatment and 100% were HCV RNA–negative and achieved 12‐week sustained virologic response. The estimated GFRs at end of treatment and 12‐week posttreatment were 67 ± 21 mL/min/1.73 m² and 67 ± 17 mL/min/1.73 m², respectively. Four recipients developed acute rejection. Kidney transplantation from HCV‐infected donors to HCV‐negative recipients should be considered in all eligible patients.