A retrospective analysis was performed of all SAEs and SARs reported related to tissues (13 years) and organs (5 years) since the implementation of the BV system (2008 for tissues, 2016 for organs) until 2020.

The definitions of SAE and SAR were those described in Directives 2004/23/EC (17) and 2010/53/EU (18). In brief, an SAE (risk of serious harm) is any untoward occurrence associated with the procurement, testing, processing, storage, and distribution of tissues or organs that might lead to a serious complication in the living donor or the recipient. An SAR (serious harm) refers to an unintended response in the living donor or the recipient that might be associated with any stage of the donation–transplantation chain, or to the quality and safety of tissues or organs, and is considered a serious complication. A serious complication consists of the transmission of communicable diseases, death or life-threatening, disabling or incapacitating conditions, or which might result or prolong hospitalization or morbidity.

Data were obtained from the Catalan BV Registry (rBioVc) (21), when a BV notification only involved Catalan centers, and from the ONT BV registry (Figure 2) when centers from other regions were affected. Other sources of information were the Donation and Transplantation Registry of Catalonia (rDTx) and the patients' electronic health records (HC3) of the Catalan Health Service.

The study protocol was approved by the Ethics Committee of the Vall d'Hebron University Hospital [reference PR(BST) 323/2016)]. All data were processed according to Regulation (EU) 2016/679 of the European Parliament and of the Council (22), the provisions of the Spanish Organic Law 3/2018 (23), and other applicable regulations on data protection.

Variables collected for SAEs included the reporting criteria (Figure 3), from the Eustite Project (24) for tissues and the Efretos project (25) for organs. Other variables included were as follows: the reporter; the risk; the stage; the cause; the number of centers involved (for organs); and the actions proposed by the BV advisory committee after investigation.

SARs were described according to the organ or tissue recipient with SAR, the type of SAR (as per the Notifylibrary taxonomy (26, 27)), detection time, and imputability [based on the Eustite project for tissues (24) and the Disease Transmission Advisory Committee (DTAC) (28) for organs] (Figure 4). In process-related issues, imputability was classified as “certain-process related”.

In order to prioritize actions once cases were closed, harmful impact was calculated (actual for SAR or potential for SAE) by multiplying the likelihood of recurrence and the highest score of consequence (for the individual, the system, or the distribution of tissues and organs). These tools are those proposed by the Vigilance and Surveillance of Substances of Human Origin (SoHO V&S) (29) project and the Eustite project (24). The impact matrix classification table applied in this study has four levels: minor (0–3); moderate (4–6); moderate/high (8–9); or catastrophic/extreme (10–20). Finally, the preventability capacity (considered when changing or implementing a test or procedure could have avoided the notification) was considered.

Qualitative variables were described as frequencies, percentages and per thousand. The incidence of SAEs was calculated by dividing the number of SAEs recorded during the study period by the number of donations registered within the same time frame. In contrast, the incidence of SARs was calculated as the number of patients with certain, probable, and possible (CPP) SARs notified during the study period, divided by the number of transplants registered within the same time frame. The potential for disease transmission was calculated by dividing the number of recipients with a proven, probable, or possible SAR by the total number of recipients at risk. In addition, the mortality rate was calculated as the number of deaths divided by the total number of transplants.

Qualitative variables were compared using the chi-square test, and the significance threshold was set at a two-sided alpha of 0.05. Statistical analyses were performed using STATA 17 and Microsoft Excel.

Between 2008 and 2020, 34,306 tissues donors and 149,891 tissues were distributed for clinical use. Between 2016 and 2020, 2,287 organ donors were registered and 5,569 organ transplants were performed (Supplementary Table S1). During the corresponding period, 154 and 125 BV notifications related to tissues and organs were made, respectively (an average of 12 notifications per year for tissues and 25 for organs). Regarding tissues, 118 (77%) notifications were classified as SAEs and 36 (23%) as SARs. With respect to organs, 72 (58%) notifications were SAEs and 53 (42%) were SARs. The imputability of SARs was deemed CPP in 35 tissue recipients and 49 organ recipients.

Of the 118 SAEs, more than half were reported by the TE and the most common criterion for reporting (73.7%) was an unexpected result from donor testing or tissue culture that compromised the quality or the safety of the tissue after it had been distributed (mainly corneas due to their expiry date). In contrast, system, equipment, and material failures and human errors accounted for only 13% of SAEs (Table 1).

The potential impact of SAEs was mostly moderate (97%) and only two had an impact on tissue supply (28 corneas were discarded due to a disqualified incubator and 40 processed bone donors immobilized under the suspicion of a contaminated processing solution). The potential individual impact was upon 363 tissue recipients and 97 organ recipients (Figure 5). A total of 216 actions were implemented and 31 (26%) SAEs were considered preventable exploring the following actions: (1) change from Rapid Plasma Reagin test to Treponema pallidum hemagglutination assay (TPHA) before donation (2021); (2) screen all tissue donors using hepatitis B virus nucleic acid testing (HBV NAT); (3) incorporate a checklist of standard operating procedures (SOPs) for distribution; (4) include final validation of a tissue before distribution; and (5) intensify personnel training to prevent human errors (Table 2 and Supplementary Table S2).

Of 36 SARs reported, 83% involved recipients of ocular and musculoskeletal tissue and more than half (61.1%) consisted of suspected donor-transmitted infections (Table 3). For ocular infections, fungal infection was predominant before day 90. Among recipients of musculoskeletal tissues, bacterial infections before day 30 were the most frequent (Supplementary Table S3). The second type of SAR in frequency was graft failure, occurring up to day 150 after cornea transplantation and within the first 40 days after the transplantation of cardiovascular tissue. There was one late tendon graft failure occurring on day 300.

Imputability was considered unlikely only in one case (evidence clearly showed that the patient had a predisposing condition). Among the the 35 SAR with CPP imputability, 92% deemed to have a moderate impact. Only in three recipients was the impact considered moderate/high, corresponding to two recipients of cardiovascular tissue and one recipient of a corneal transplant. Only three non-transmissible SARs (8%) modified SOPs on final cornea quality validation and preservation and packaging verification (Supplementary Table S3).

From a total of 72 SAEs, 44% were reported by the transplant center (Table 4) followed by the TE (30%). A malignancy identified in the donor at the pathology/autopsy examination after solid organ transplantation had taken place was the most frequent reporting criteria (40%), followed by donor blood testing (28%) due to positive HBV NAT, positive syphilis serology, and parasites screening (results after donation). Therefore, the main cause for opening a notification was the identification of a disease in the donor unknown before transplantation (67%), while system or equipment failure and human errors accounted for 33% of cases. Supplementary Table S4 summarizes the frequency of SAEs according to donor type, which was statistically significantly lower in living vs. deceased donation (p < 0.0001).

The potential impact of SAEs was mostly moderate (92%) upon 156 organ and 4 musculoskeletal tissue recipients (Figure 5); however, 20 corneas were considered suitable despite malignancy, because malignancy does not contraindicate cornea transplantation. There were only 2 (3%) moderate/high impact cases due to the identification of an active malignancy in the donor (enteral adenocarcinoma and thyroid cancer) (Supplementary Table S5). None of the SAEs had any impact on the donation system or on organ supply.

A total of 109 actions were implemented while 20 (28%) SAEs were deemed preventable executing the following actions: (1) results of T. pallidum antibodies available before transplantation; (2) requirements for blood testing, including automatic transcription (implemented in 2022); (3) elaboration of algorithms for decision-making when new techniques are incorporated in the serology or HLA lab (2019); (4) training staff for a correct donor characterization; (5) review, change, and incorporation of a checklist of SOPs for blood sampling, packaging, and preservation; and (6) creation of an urgent alert from the pathology department to the BV system when results compromise the recipient’s safety (Table 5).

Regarding donor malignancies (seven were classified as of unacceptable risk according to the Council of Europe Guide (30)), no transmission occurred after a follow-up of 2–5 years. However, for the mesenteric adenocarcinoma SAE, a liver-kidney transplant was explanted 3 weeks after transplantation. None of the recipients developed a SAR.

From 53 SARs reported, 83% consisted of complications developed by kidney and liver recipients, and more than half were donor-transmitted infections or malignancies, unknown at the time of donation (Table 6), with 43% non-transmissible SARs (undue exposure to risk, explant, delayed graft function, surgical site complications, and detrimental immunization, mainly classified as process-related). Detection time (Supplementary Table S6) for bacterial infection was less than 14 days, 30–850 days for viral infections, 5–120 days for parasites, and less than 1 week for fungal infections, except for a case of histoplasmosis (day 1700). The malignancy detection time varied depending on the type of cancer, from kidney and urinary tract and blood and lymphoid (46–90 days), lung and lower respiratory system (1 year), gastrointestinal (2 years), and a case of cholangiocarcinoma (4 years), which was deemed donor-derived rather than donor-transmitted.

Imputability was excluded in 4(8%) SARs (two infections and two malignancies) and among the remaining 49 CPP SARs, 36 (74%) were certain (including 23 process-related cases) showing an unexpected infectious transmissions of 0.23% and malignancies 0.16%. Taking into account imputability (Supplementary Table S6), 13 donors transmitted an infection to 15 out of 40 (38%) recipients at risk, which became fatal in 3 (20%) cases and 9 donors transmitted a malignancy to 11 out of 26 (42%) recipients at risk, with a fatal outcome in 6 (55%) cases. In fact, among infectious disease transmissions, only one donor transmitted parasites to more than one recipient, and among malignancies, only soft tissue/sarcoma and gastrointestinal malignancy were transmitted (Supplementary Table S1).

In terms of the impact of SARs, 78% were deemed to have moderate impact, 8 (16%) moderate/high impact, and 2 (4%) extreme impact (Supplementary Table S6); two kidneys were explanted 1 month after transplantation due to a donor autopsy revealing a lung malignancy. Both recipients were re-transplanted 3 and 4 years after explant and none had malignancy transmission after 7 years of close monitoring. Significant actions due to non-transmissible SARs included a double verification to include recipients on the waiting list, review of HLA SOPs and staff training, inclusion of the ABO blood group in the verification checklist before the transplant, ensuring and confirming the laterality terminology, and promoting continuous training on SOPs for organ procurement and packaging.

During the study period, the incidence of SAEs and CPP SARs related to tissue donations and transplants was 3.44‰ and 0.22‰, respectively, while the incidence of SAEs and SARs related to organ donations and transplants was 31.48‰ and 8.8‰, respectively.