Unintended transmission of hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), and human T lymphotropic virus (HTLV) from deceased organ donors is a rare but serious complication of organ transplantation.1 This risk is minimized by performing relevant laboratory-screening investigations in deceased donors before implantation of their organs. Currently available screening strategies cannot completely discount the presence of a recently acquired viral infection, and considerable importance is attached to the identification of donors with a history of increased risk behavior (IRB) associated with the acquisition of HCV, HIV, HBV, and HTLV.1-4 Although the discard of organs from those with a history of IRB would minimize disease transmission, it would markedly reduce the number of transplants performed. Consequently, the risk of disease transmission from donors with IRB needs to be balanced against the potential benefits of organ transplantation.
Solid organ donors who have a history of prior or current intravenous drug use (IVDU), or of recent or historical imprisonment, and those who have a history of high-risk sexual behavior are viewed at greatest risk of transmission of blood-borne viral (BBV).2,3 In the United Kingdom (UK), current guidance from the Advisory Committee for the Safety of Blood, Tissues and Organs and the European Directive on Organ Donation requires that detailed information on “behavioral history that could have put the donor at an increased risk of blood borne viruses” be obtained.5 The information needed includes “questions about risk behaviors such as recreational drug use, men who have sex with men (MSM), and risks such as accidental body fluid exposure.”5 UK guidance on donor assessment is consistent with that in the United States where the need to assess behavioral risk factors for a donor to be at increased risk of transmitting HIV, HBV, and HCV is highlighted.2 The donor history with respect to such IRB also provides an important context for the interpretation of the results from microbiological screening for HIV, HCV, HBV, and HTLV.3,5,6 Current screening tests for viral markers have limited sensitivity, and serological screening may result in an infective window period of up to 70 days after infection when antibodies to virus are undetectable.6
We report the UK experience of deceased organ donors, both potential and actual, with a history of IRB, highlighting the overall prevalence and types of IRB. Our aim was to establish the impact of IRB on organ donation and utilization, as well as on their transplant recipient outcomes.
MATERIALS AND METHODS
Identification of Deceased Organs Donors With IRB
The UK Transplant Registry was examined to identify all deceased organ donors between January 1, 2003, and December 31, 2015, who had a history of any 1 of the following IRB: IVDU, current or previous imprisonment, MSM, sex in exchange for money or drugs, and high risk sexual partner (defined as a sexual relationship with any of the previously mentioned increased risk groups). For the purposes of this study, “potential donors” were defined as deceased donors for whom consent/authorization for organ donation had been obtained, “actual organ donors” as deceased donors who had 1 or more solid organs removed for transplantation on the basis that recipient centers had provisionally agreed to use them for transplantation, and “utilized organ donors” as actual organ donors whose organs where eventually transplanted. The decision as to whether or not a potential donor proceeds to organ donation is dependent on transplant clinicians at individual transplant centers indicating that they are willing to accept the organs for transplantation. There are no centralized clinical advisors involved in this decision.
In the UK, a donor transplant coordinator (designated in 2008 as a Specialist Nurse in Organ Donation) is required to enquire from the next of kin, medical notes and the potential donor’s family doctor, whether there is a history of IRB and record these findings. Additional UK guidance published in 2000 highlighted the requirement to screen potential organ donors for behavior associated with BBV.
Free text entries of all potential donors were searched using the terms “intravenous drug use,” “sex worker,” “men who have sex with men,” and “prison.” All common abbreviations, misspellings, synonymous terms, and colloquialisms of the above search terms were also searched. Donors with a history of IVDU and imprisonment were subcategorized based on whether or not they had been an IVDU or imprisoned during the preceding 12 months. Donors with a history of high-risk sexual behavior were subcategorized according to the type of behavior into any 1 of “high risk partner,” “sex worker,” and “prior high risk partner.”
It is important to note that a number of patients did not fall into the category of potential donors because formal consent for donation was not sought for a variety of reasons that included a belief by the clinicians caring for the patient that the patient’s IRB would exclude organ and tissue donation. Information on the number of patients that did not progress to become potential donors for the entire study period (2003-2015) was not available but the potential donor audit (a prospective registry of all patients younger than 80 years who died in critical care units of acute UK hospitals, irrespective of their medical suitability to become organ donors) was interrogated to obtain information on patients excluded from the present analysis. Between January 1, 2009, and December 31, 2015 there were 12 040 potential donors analyzed in the present study, and during the same period the Potential Donor Audit showed that 1022 patients with an identified IRB (89% IVDU) did not get consented for organ donation for a variety of reasons that included IRB. In 86 patients excluded from the present study, IVDU was stated explicitly as a reason why the patient’s family was not approached for consent for organ donation.
Identification of Recipients of Organs From Donors With IRB
The UK transplant registry was examined to identify recipients of organs from donors with IRB and information on outcome (patient and graft survivals) obtained. UK transplant centers are required to notify National Health Service Blood and Transplant (NHSBT) of any potential donor-derived disease transmission and adverse events relating to the donation process. This reporting requirement became mandatory when the new European Union Organ Donation Directive guidelines came into effect (2010) and was written into UK law in the Quality and Safety of Organs for Transplantation Regulations (2012). Before 2010, recipient centers were expected, according to UK guidance, to report any adverse outcomes in recipients relating directly to the organ donation process to NHSBT. Details of any donor transmitted infections were collected from a designated transplant incident reporting registry held by NHSBT.
Univariate analysis comparing clinical characteristics between IRB and non-IRB potential donors, who were seronegative for BBV, was carried out using Student t test for approximately normal continuous data, and the Mann-Whitney U test for abnormal continuous data. Categorical comparisons were made using the χ2 test.
Kaplan-Meier curves were used to show death-censored graft survival and patient survival and the univariate log-rank test was used to compare unadjusted survival rates.
Cox proportional hazards regression model and a logistic regression model were fitted in a stepwise selection method to control for potentially confounding factors. Donor-related variables considered for inclusion in the multivariate model were donor age, donor type, ethnic group, sex, medical history of diabetes and hypertension, liver disease, cardiac disease, smoking history, and whether the donor had a history of IRB. Recipient factors included were age, ethnicity, sex, primary renal disease, HLA mismatch level, and cold ischemic time.
All analyses were performed using Statistical Analysis System (SAS) (version 9.3) and P values less than 0.05 were deemed to be statistically significant.7
HLA mismatch level (levels 1-4) was defined according to UK allocation policy for kidneys from brain-death donors and was based on the mismatch between donor and recipient.8
The United Kingdom Model for End-Stage Liver Disease score was used when assessing differences in liver recipient characteristics. This score is calculated based on the patient’s international normalized ratio, serum creatinine, serum bilirubin, and serum sodium.9,10
One or more IRB was identified in 659 (3.8%) of potential deceased donors, and 454 (3.6%) of actual organ donors. Of the potential donors with a history of IRB, 47% had a history of IVDU, 33% a history of imprisonment, 10% were MSM, and 9.9% a history of high risk sexual behavior. For actual donors with a history of IRB, 41% had a history of IVDU, 37% had a history of imprisonment, and 21% had a history of high risk sexual behavior, and these proportions did not differ significantly from the behaviors in potential donors (P = 0.147).
Organ Donors Who Were Seropositive for HIV, HCV, HBV, and HTLV
Overall, 285 (1.7%) of potential organ donors were found to be seropositive for BBVs markers. One hundred four (36.5%) seropositive potential donors proceeded to organ donation; in contrast to the 78% conversion rate observed in seronegative potential donors (P < 0.001). Organs from 81 (77.8%) of the seropositive organ donors were subsequently transplanted, compared with 95.7% of seronegative organ donors (P < 0.001).
Half (50.5%) of potential donors who were seropositive for viral infection had a history of IRB, and in most (78.5%) this included IVDU. A history of imprisonment, MSM, and high-risk sexual behavior was less common (16.7%, 2.7%, and 2.1%, respectively). The clinical characteristics of potential and actual seropositive donors are shown in Table 1. Positive serology for HCV was more common in donors with a history of IRB. In contrast, markers of HIV, HBV, and HTLV were all more common in seropositive donors with no history of IRB (Table 1).
The types of organs from seropositive organ donors that were used for transplantation differed according to whether or not there was a history of IRB. The 62 organ donors with a history of IRB provided 48 livers and 11 kidneys that were used for transplantation, whereas the 42 donors with no history of IRB donated 25 livers and 32 kidneys that were transplanted (P < 0.001).
IRB and Organ Donation in Donors Who Were Seronegative for Viral Infection
To examine the association between IRB and organ donation, all seropositive potential donors were excluded from subsequent analysis. After exclusion, there were 16 977 remaining potential donors of which 12 737 (75%) proceeded to organ donation (Figure 1). A history of IRB was identified in 515 (3%) of potential and 392 (3%) of actual organ donors, suggesting that overall, a history of IRB did not adversely influence the decision to proceed to organ donation. 25% of potential donors with no history of IRB and 24% of those with a history of IRB did not proceed to donation (P = NS). Potential donors with a history of IRB were, when compared to those with no history of IRB, much younger, and significantly less likely to have hypertension, cardiac disease and diabetes (Table 2). Potential donors with IRB were, however, more likely to be smokers and to have a history of alcohol abuse.
There were significant differences in the conversion rate from potential to actual donors according to the type of IRB (Figure 2). Potential donors with a history of IVDU were less likely to proceed to organ donation than donors with no history of IRB and this effect was most marked in potential donors with a history of recent rather than historical IVDU. Those with a history high-risk sexual behavior alone were as likely to proceed to donation as those with no history of high risk sexual behavior (Figure 2). History of imprisonment (previous or current) alone was associated with an increased rate of proceeding to donation compared to donors with no history of IRB (Figure 2). However, when a logistic regression model was fitted to adjust for the significant differences in age and co-morbidity between donors with or without a history of IRB, IRB was associated with significantly fewer potential organ donors becoming actual organ donors (odds ratio = 1.580 (95% CI 1.273-1.962, P < 0.001).When the logistic regression model was fitted for the different types of IRB, IVDU (both recent and historical) was associated with significantly fewer potential organ donors becoming actual organ donors (odds ratio, 3.552; 95% confidence interval [CI], 2.373-5.315; P < 0.001 and odds ratio, =1.984; 95% CI, 1.205-3.268; P = 0.007, respectively) (Table 3).
The number of potential donors with a history of IRB increased markedly over the 13-year study period, and the percentage of donors proceeding to donation also rose in the latter part of the study period (Figure 3).
Clinical Characteristics of Actual Organ Donors With History IRBs
Potential donors with a history of IRB, that proceeded to become actual organ donors were younger (39.8 ± 12.6 years vs 44.3 ± 11.6 years; P < 0.001) and more likely to be donation after brain-stem death (DBD) than donation after circulatory death (DCD) donors (36.2% DCD vs 82.9% DCD; P < 0.001) than those potential donors with IRB who did not proceed to organ donation.
The clinical characteristics of the 392 actual organ donors with a history of IRB, along with the clinical characteristics of all other deceased organ donors are shown in Table 4. Actual organ donors with a history of IRB were younger, more often men and more likely to be of an ethnic minority other than white. Organ donors with a history of IRB were more likely to have a history of smoking and of alcohol abuse (Table 4).
Clinical Characteristics of Recipients Receiving Organs From Donors With IRB
Over the 13-year study period, a total 1091 transplants were carried out using organs from seronegative deceased donors with a history of IRB (624 kidney, 278 liver, 63 heart, 39 lung (including 1 lung pair), 2 heart and lung transplants, 84 pancreases, and 1 bowel transplant).
Recipients of kidneys from donors with a history of IRB were younger, more often of nonwhite ethnicity and less well matched for HLA than recipients of kidneys from donors with no IRB (Table 5). Recipients of kidneys from donors with IRB spent a similar amount of time on the transplant waiting list and had a similar duration of dialysis pretransplant when compared with those who received kidneys from donors without IRB. Recipients of kidneys from donors with IRB had similar graft and patient survival to those who received kidneys from all other deceased donors (Figure 4A). When the recipients of the different types of IRB were compared to all other recipients, a donor history of recent IVDU did not adversely influence patient or graft survival (Figure 4B).
Recipients of livers from donors with a history of IRB were older, more often men, had a lower UK End-Stage Liver Disease score, and more often HCV-positive than recipients of livers from donors with no IRB (Table 6). Similarly, patient and graft survival after liver transplantation was comparable for recipients of livers from donors with and without IRB (Figures 5A and B).
Because of the differences in donor and recipient demographics between recipients that received organs from donors with a history of IRB compared to those that did not, a Cox proportional hazards regression model was fitted to adjust for donor and recipient age, donor history of hypertension, HLA mismatch, cold ischemic time, and primary recipient disease. This showed that patient survival after kidney transplantation was not adversely affected by a donor history of IRB (Table S1, SDC,http://links.lww.com/TP/B422). After assessing whether the different subtypes of IRB adversely impacted on transplant outcome the multivariate analysis indicated recipients of kidneys from donors with high-risk sexual behavior had significantly worse patient survival than those who received kidneys from donors with no history of high-risk sexual behavior, even after adjusting for donor and recipient factors. Each of the high-risk sexual behaviors was assessed in turn, and this revealed that it was only those who received kidneys from donors with a high-risk sexual partner that had worse patient survival.
From the 1091 organ transplants from donors with IRB, 1 liver recipient and 2 renal recipients (all from the same organ donor) developed donor-derived HCV infection. The donor of the organs had a history of recent IVDU, and tested negative for HCV antibody at time of donation. Retrospective testing of the donor serum obtained at donation was positive for HCV Ribonucleic Acid. The liver recipient was known to be HCV positive at time of transplantation, but it was noted that the predominant HCV genotype changed from genotype 1 pretransplant to donor genotype 3 after transplant. The 2 renal recipients were both HCV negative before transplantation.
There were no reported unexpected HIV, HBV, or HTLV transmissions from these IRB donors.
Routine screening of all potential organ donors for a history of IRB to determine risk of transmission of BBV infection is routinely undertaken in most countries to help inform the decision on organ usage. The present analysis provides insight on the impact of this policy on organ donation and utilization in the UK, where the prevalence of BBV infection is slightly lower than that in the United States and broadly similar to Western Europe.11-14
Around 4% of all potential organ donors, for whom consent for donation was obtained, had a history of IRB and 22% of these (2% of all potential donors) were seropositive for blood BBV (mostly HCV), at the time organ donation was being considered and over half had a history of IRB. Positive serology for blood borne viruses may indicate a very high risk of disease transmission during transplantation, and enables an informed decision on whether to proceed with organ donation, and if so, to allocate organs to appropriate potential recipients; in the majority of cases the recipients are likely to be selected on the basis that they already have infection corresponding to that identified in the donor.
In the present study, we were particularly interested in the extent to which IRB in seronegative potential donors impacted on organ donation and transplantation. Overall, around three quarters of all potential organ donors in the UK proceeded to become actual organ donors, on the basis that transplant implanting centers had provisionally accepted them for transplantation. A history of IRB (all types) was not associated with a reduction in the proportion of potential donors that proceeded to become organ donors. However, a history of IVDU accounted for nearly half of all IRB and was associated with a relatively small but significant reduction in the proportion of potential donors proceeding to donation, especially when the drug use may have been recent.
Potential donors with IRB were significantly younger and had less additional comorbidity than those with no IRB, and when these variables were taken into account by logistic regression analysis, IVDU (both recent and historical) were associated with donors not proceeding to become actual organ donors. Our analysis of the potential donor audit (a prospective registry of all patients aged <80 years who died in critical care units of acute UK hospitals, irrespective of their medical suitability to become organ donors) indicated that a large number of these identified registry patients did not get consented for organ donation because of their history of IRB (in particular IVDU).
The number of potential donors with IRB in the present study increased markedly over the 13-year study period. This likely reflects, for the most part, a true increase in the number of such donors over time, in line with the general trend toward increased consideration of organs from other types of high-risk donor.15 However, it is also likely that some of the increase in potential donors with IRB over time may be attributable to a bias in data capture, as clinical practice in organ donor screening by transplant coordinators and documentation became more standardized.
Although the risk of disease transmission in seronegative donors with IRB is very low, not all transplant centers routinely assess recipients for graft-derived acquisition of BBV disease and consequently the present study may provide an underestimate of disease transmission from donors with IRB. Although seronegative donors with a history of IRB represent a small proportion of the total donor population they made a significant contribution to organ transplantation in the UK over the 13-year study period, providing organs for over a thousand transplants.
There were 3 confirmed transmissions of HCV to 2 renal transplant recipients and 1 liver transplant recipient. All 3 episodes of disease transmission originated from the same donor, who was known to be an active IVDU at time of donation. Using standard serological testing the window period from infection with HCV to detection by antibody assays is around 70 days6,16–18 and with nucleic acid technology (NAT) is 3 to 5 days.6,16,18 However, both serological testing and NAT testing carries the risk of false-positive results and hence the unnecessary discard of potentially infection free organs from potential donors. NAT testing is only currently available in selected UK centers and recent evidence suggests that NAT testing would improve utilization of organs from IRB donors, but not from donors with no history of IRB.6 Hence, even when NAT testing is available, a thorough history regarding IRB is still important to aide interpretation of positive results.
As might be expected, recipients of organs from seronegative donors with IRB had transplant outcomes (patient and graft survival) comparable to recipients of organs from deceased donors with no history of IRB, even after adjustment for differences in donor and recipient demographics. However, those who received kidneys from donors with a high-risk sexual partners had worse patient survival than all other deceased donors. The exact cause of this remains unclear. When the causes of renal recipient death in this cohort were examined, no deaths (n = 8) were on inspection attributable to disease transmission from the donor (n = 1 gastrointestinal hemorrhage, n = 1 hemorrhage from graft site, n = 1 septicemia, n = 1 liver viral hepatitis, n = 2 posttransplant lymphoproliferative disorder, n = 1 nonlymphoid malignant disease, n = 1 ischemic heart disease). The case of viral hepatitis was fulminant liver failure secondary to HCV genotype 1b, which was already present in the recipient before transplantation. There was no significant difference in graft or patient survival in recipients of livers from donors with high-risk sexual behavior and all other deceased donors.
The comparison of recipient characteristics according to whether or not they received a kidney from a donor with a history of IRB revealed that recipients of kidneys from donors with IRB were significantly younger and significantly more likely to be of nonwhite ethnicity. Donors with a history of IRB were also significantly younger and of nonwhite ethnicity than all other deceased donors, and kidney allocation and acceptance policies in terms of age, blood group and HLA matching would likely explain the differences observed in recipient demographics. In support, it was notable that for liver transplant recipients, where HLA matching is not undertaken there was no significant difference in the ethnicity of recipients according to whether or not they received a liver from a donor with IRB. Because kidney donors with IRB were significantly younger than other deceased kidney donors, and recipients of kidneys from younger donors have improved transplant outcomes, it might have been expected that transplant outcomes would have been better in recipients of kidneys from donors with IRB.15,19 The number of recipients of kidneys from donors with IRB in the present study may not have been sufficient to demonstrate the advantage of younger donor age on transplant outcome.
The present study is the first to report in detail on different categories of IRB in a national cohort of deceased organ donors, and provides important information on which to base future transplant policy for managing the risk of disease transmission. The numbers presented likely represent an underestimate of potential donors with IRB in the donor population, because of underreporting. This is evidenced by the small number of reported MSM in the registry (0.44%), whilst estimates from a recent US census analysis and meta-analysis estimated that around 3.9% of the US adult male populations are MSM, and in the UK it is estimated that 2.0% to 2.5% of the adult male population are MSM.20,21
Research suggests that a patient would be willing to accept a kidney from a donor with IRB if the organ was deemed otherwise healthy22: individuals are more concerned about the perceived poor quality of the organ and the risk of disease transmission rather than having a prejudice or concern about a particular type of IRB per se.22
Although the present study indicates that a history of IRB, particularly IVDU, in seronegative potential donors is associated with a reduction in organs being accepted for transplantation, such donors represent a valuable source of organs for transplantation and the risk of disease transmission in the context of UK blood borne virus epidemiology is relatively small. Moreover, recent advances in the management of transmissible viruses particularly HCV, means that even if viral disease transmission occurs it can in many cases be successfully managed.23 It has also been suggested that kidneys from seronegative donors with a history of IRB may be a valuable source of organs for potential recipients with an increased likelihood of death whilst on the waiting list.24-26 When organs from donors with a history of IRB are used for transplantation it would be prudent for all centers to test recipients within an appropriate period after transplantation to exclude donor derived infection.
Around 4% of UK deceased donors have an identifiable history of behavior associated with an increased risk of blood borne transmissible viral infection, but are seronegative at time of donation. Three quarters of such donors provide organs for transplantation with good transplant outcomes, and apparently low risk of disease transmission. Recent advances in the treatment of viral disease, particularly HCV, further reduce the risks associated with disease transmission. Donors with a history of IRB provide a valuable source of organs for transplantation with good transplant outcomes and there is scope for increasing the use of organs from donors with IRB, in particular for donors with a history of IVDU.
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