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Donor-derived disease transmission is increasingly recognized as a source of morbidity and mortality among transplant recipients. Policy 4.7 of the Organ Procurement and Transplantation Network (OPTN) currently requires reporting of donor-derived events. All potential donor-derived transmission events (PDDTE) reported to OPTN/UNOS were reviewed by the Disease Transmission Advisory Committee (DTAC). Summary data from January 1, 2005–December 31, 2007, were prepared for presentation. Reports of PDDTE have increased from 7 in 2005, the first full year data were collected, to 60 in 2006 and to 97 in 2007. More detailed information is available for 2007; a classification system for determining likelihood of donor-derived transmission was utilized. In 2007, there were four proven and one possible donor-derived malignancy transmissions and four proven, two probable and six possible donor-derived infectious diseases transmissions. There were nine reported recipient deaths attributable to proven donor transmissions events arising from eight donors during 2007. Although recognized transmission events resulted in significant morbidity and mortality, transmission was reported in only 0.96% of deceased donor donations overall. Improved reporting, through enhanced recognition and communication, will be critical to better estimate the transmission risk of infection and malignancy through organ transplantation.
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Solid organ transplantation has given life-extending benefit to many patients with end-stage organ failure and a large majority of patients have a functioning organ at the end of 1 year (1). But, as with most medical interventions, there is a risk of serious complications. One potential complication is disease transmission (e.g. infection, malignancy) from the donor to the recipient(s). Donor-transmitted diseases are typically ‘expected’ when routine testing shows donor infection (e.g. seropositivity) and recipient susceptibility (e.g. seronegativity) before transplantation. When transplants are performed under these circumstances, the urgent need may be deemed to outweigh the expected risk and are considered acceptable medical practice. Careful monitoring of these patients and the use of prophylaxis or treatment may reduce the frequency or severity of these transmitted diseases (e.g. cytomegalovirus [CMV], Epstein–Barr virus [EBV] and hepatitis B virus [HBV]) and may permit the use of these organs.
Unfortunately, diseases that are not expected or are not identified in the donor can also be transmitted to the recipient(s) with potentially fatal results. Recent high profile transmission events include human immunodeficiency virus (HIV), hepatitis C virus (HCV), lymphocytic choriomeningitis virus (LCMV) and a related arenavirus, tuberculosis (TB), West Nile Virus, rabies, Chagas disease, leukemia and lymphoma (2–11). Several OPTN policies have been enacted with the goal of reducing the risk of potential disease transmission. Current OPTN policy mandates the pathogens for which potential donors must be routinely screened (i.e. HIV, HBV, HCV, syphilis, human t-lymphotropic virus (HTLV), CMV, EBV; in addition blood and urine must be cultured for bacteria in donors hospitalized ≥72 h) (12). Policy also requires acquisition of the donor's medical and social history; unfortunately the quality of these data is highly variable and dependent on how familiar the data source is with the donor. Other known conditions that may be transmitted by the donor organ must also be communicated to recipient transplant center personnel, who may accept the organs for transplant as appropriate with the informed consent of the recipient(s) (Table 1) (13). Further, OPTN policy requires informed consent of the recipient of organs from donors at ‘high risk’ for HIV transmission based on the Public Health Service (PHS) definition (14).
Table 1. Known conditions that may be transmitted by the donor organ that must be communicated to the transplant center prior to transplantation (13)
|• Unknown infection of central nervous system (encephalitis, meningitis)|
|• Suspected encephalitis|
|• Hepatitis C|
|• Herpes simplex encephalitis or other encephalitis|
|• History of JC virus infection (causes progressive multifocal leukoencephalopathy)|
|• West Nile virus infection|
|• Cryptococcal infection of any site|
|• Creutzfeldt–Jacob disease|
|• Other fungal or viral encephalitis|
|• Bacterial meningitis|
|• Infection with HIV (serologic or molecular)|
|• Active viremia: herpes, acute EBV (mononucleosis)|
|• Serologic (with molecular confirmation) evidence of HTLV-I/II|
|• Active hepatitis A or B|
|• Infection by: Trypanosoma cruzi, Leishmania, Strongyloides, Toxoplasmosis|
|• Active Tuberculosis|
|• Bacterial or fungal sepsis (e.g. candidemia)|
|• Multisystem organ failure due to overwhelming sepsis, such as gangrenous bowel|
|• Malignancies-other active malignant neoplasms,|
|• Melanoma, Merkel cell, including Kaposi's|
|• Hodgkins’ disease and non-Hodgkin's lymphoma|
|• Multiple myeloma|
|• Aplastic anemia agranulocytosis|
|• Miscellaneous carcinomas|
|• Any new conditions identified by the CDC as being a potentially communicable disease|
The Disease Transmission Advisory Committee (DTAC) was first established in 2005 as an advisory group to the OPTN/UNOS Operations Committee to identify and review potential donor-derived disease transmission events. The DTACs core tasks include:
Estimating the risk within the OPTN of donor-derived disease transmission.
Accumulating evidence necessary for this estimation through review of cases reported to UNOS as the OPTN contractor.
Providing initial notification to public health agencies when there are suspected transmission of reportable diseases.
Reporting the Committee's aggregate findings and observations to the transplant community.
Providing recommendations to the OPTN on policy with the goal of reducing donor-derived transmission events.
The Committee comprises a broad representation of the transplant and organ procurement communities, as well as ex officio representatives from the Centers for Disease Control and Prevention and the Health Resources and Services Administration's Division of Transplantation. It includes experts representing the fields of infectious diseases, pathology, donor evaluation and management and organ transplantation. The authors of this article were members of the Committee at the time that the article written.
OPTN Policy 4.7 requires that ‘when a transplant program is informed that an organ recipient at that program is confirmed positive for or has died from a transmissible disease or medical condition for which there is substantial concern that it could be from donor origin, the transplant program must notify by phone and provide available documentation, as soon as possible and not to exceed one complete working day, to the procuring Organ Procurement Organization (OPO)’ which then must submit the finding to the OPTN (15). These reports are submitted through the OPTN Patient Safety System (https://portal.unos.org/index.aspx). When these notifications are received by UNOS staff, redacted initial reports and supporting data are prepared that remove all patient-, OPO- and transplant center-identified information. These reports are then uploaded onto a password-protected secure web site accessible to the members of the DTAC, and an e-mail is sent to the DTAC members alerting them of the new report. The Committee then engages in an e-mail-based confidential medical peer review process. DTAC recommendations about additional information that may be needed to determine if a transmission has occurred are made within 24–48 h of the initial report. Further rounds of e-mail communication occur as additional case details are received from the OPO or recipient transplant centers. If warranted or required (e.g. nationally notifiable infectious diseases as defined by the CDC), local, state and federal (CDC) health authorities are involved. Similarly, case-specific conference calls are sometimes initiated to facilitate communication among the transplant centers, OPOs, health authorities and DTAC. OPOs are required to submit a report 45 days after the initial report that summarizes the findings of their investigations of each reported cases. These 45-day reports are reviewed by the DTAC as well to determine if additional information is needed. All communication between the OPOs, transplant centers and DTAC is coordinated by the DTAC's UNOS staff liaisons. The Committee is currently developing a process to ensure that the OPOs and transplant centers are made aware of the determination of the Committee once the 45-day report has been reviewed. The Committee meets at least monthly via conference call to discuss cases currently under review. Additionally, twice-yearly in-person meetings are convened to further discuss events, tasks and policy issues assigned to the DTAC by the OPTN/UNOS Board of Directors.
The DTAC began reviewing reports of potential donor-derived transmission events (PDDTE) in late 2004. This report summarizes the results of reviews since that time, with an emphasis on cases reported in 2007 when more detailed reviews by the Committee began.
Materials and Methods
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All PDDTE that were reported to the OPTN via the electronic Patient Safety System have been reviewed by the DTAC. An event is defined as all potential disease or malignancy transmissions from one donor to one or more recipients. All of the available data were reviewed in detail and events were categorized first as either ‘expected’ (i.e. transmission would be expected as transplantation is conducted when there were known risks) or ‘unexpected’ (see Table 2).
Table 2. Expected donor-derived disease
|Any case in which information about the potentially transmissible donor-derived disease was known before transplantation or for which there are recognized standard guidelines for routine prevention of the pathogen are available were excluded; examples include:|
| • Cytomegalovirus (CMV)|
| • Ebstein–Barr virus (EBV)|
| • Toxoplasmosis|
| • Known HBc Ab+ only|
The Committee devised a classification scheme for the events reported in 2007 and since then have further classified events as to the likelihood of being transmitted from the donor with the classifications of proven, probable, possible or excluded. (defined in Table 3). Each case was discussed by the entire Committee until a consensus classification was made. Essentially, proven transmission required identification of the same pathogen in the donor and recipient or a malignancy of documented donor origin; probable transmission was used when there was strong evidence to suggest that the pathogen or malignancy was of donor origin, but there was no documentation of donor origin and possible transmission was used when the Committee felt that the evidences suggested a transmission event but for which clear evidence of donor origin could not be determined. These categories have evolved over the period of time that the DTAC has been in existence, are working designations, and have not been formally ratified by the OPTN. The Committee has great confidence that transmission has clearly occurred in all proven cases; classification of cases as other than proven is dependent on the available data. The DTAC provides suggestions regarding additional testing to the OPO and transplant centers, but current OPTN policy does not require these groups to conduct the recommended evaluation. As such, there is no way to validate or definitively document the likelihood of transmission in every case. Last, appropriate specimens were not always available, further limiting appropriate testing required to document transmission. Descriptive statistics were calculated.
Table 3. Classification system for determining likelihood of the transmission event being donor-derived
|Proven||All of the following conditions must be met:|
|• Suspected transmission event|
|• Laboratory evidence of the suspected organism or malignancy in a recipient|
|• Laboratory evidence of the same organism or malignancy in other recipients|
|• Laboratory evidence of the same organism or malignancy in the donor|
|• If there is pretransplant laboratory evidence, it must indicate that the same recipient was negative for this organism prior to transplantation|
|Probable||Both of the following two conditions must be met:|
|• Suspected transmission event and|
|• Laboratory evidence of the suspected organism or malignancy in a recipient|
|And at least one of the following criteria must also be met:|
|• Laboratory evidence of the same organism or malignancy in other recipients;|
|• Laboratory evidence of the same organism or malignancy in the donor;|
|If there is pretransplant laboratory evidence, it must indicate that the same recipient was negative for this organism prior to transplantation|
|Possible||Suspected transmission event and|
|Laboratory evidence of the suspected organism or malignancy in a single recipient or|
|No evidence of transmission in the setting of active prophylaxis or treatment for the infection or|
|Data that strongly suggests but does not prove a transmission event|
|Excluded||Suspected transmission event and at least one of the following conditions is met:|
|• There is clear evidence for an alternative reason for the event|
|• Lack of infection with the same organism in any other recipients, from the same donor, given appropriate testing|
|• Laboratory evidence that the recipient had infection with this organism or malignancy prior to transplantation|
|Confirmed||Any case that is classified as proven, probable or possible.|
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A total of 164 events have been reported through the Patient Safety System between 2005 and 2007. There were 7 reports of PDDTE reported in 2005, 60 in 2006 and 97 in 2007. Of these reports, 10 (0 in 2005, 0 in 2006, 10 in 2007) were classified as ‘expected’ and the remainder were ‘unexpected’. Eighty-nine of the unexpected events reported were related to a potential infectious disease transmission (Table 4). This accounted for over half of all unexpected events reported (58% of 154 events: 4 in 2005, 31 in 2006 and 54 in 2007). The most commonly reported potentially transmitted infections included HCV, TB, HIV, Chagas, HBV, toxoplasmosis and West Nile Virus. There were 65 reports (42% of 154 events; 3 in 2005, 29 in 2006 and 33 in 2007) of unexpected malignancy related events made to the OPTN (Table 5). The most frequently reported potential transmissions of cancers involved renal cell carcinoma, lung cancer, glioblastoma multiforme and lymphoma.
Table 4. Reports received by the OPTN between 2005 and 2007 regarding a potential donor-derived infectious disease transmission
|Infections||Donor reports2||Confirmed recipients3||Recipient deaths4|
|Hepatitis C virus||9|| 45|| 15|
|HIV||7|| 45|| 15|
|Hepatitis B virus||6||0||0|
|West Nile virus||6||2||0|
|S. aureus in transport fluid||1||0||0|
|Totals||80 ||30 ||14 |
Table 5. Reports made to DTAC regarding a potential donor-derived malignancy transmission 2005–2007
|Malignancies||Donor reports1||Confirmed recipients2||Recipient deaths3|
|Renal cell carcinoma||25 ||3||0|
|Lung—small cell cancer||1||1||0|
|Renal Papillary adenocarcinoma||1||0||0|
|Totals||55 ||15 ||6|
Since cases reported during 2007 received greater review, the Committee was better able to classify the likelihood of transmission of these events (see Table 6). Half of the infectious disease reports (27) and 30% of the malignancy reports (10) were classified by the Committee as excluded as no transmission could be documented. Most of the excluded cases had no clear associated disease (19 cases) or had insufficient data (13 cases; most were seroconversions of single recipients with no data from the other recipients); and nine were excluded because they were reports of false-positive testing.
Table 6. 2007 confirmed transmission events
|Type||Status||Disease||Reported (time posttransplant)||No. of recipients affected1||Organs affected||No. of recipients who died|
|Malignancy||Proven||Hepatocellular CA|| 5 months||1/3||Liver||0|
| ||Glioblastoma multiforme|| 2 months||1/4||Lung × 2||1 Double lung|
| ||Lymphoma||1.5 months||4/4||Liver pancreas||4 Liver, pancreas,|
| || || || ||kidney × 2||kidney × 2|
| ||Small cell lung cancer|| 10 months||1/1||Liver||0|
|Possible||Melanoma|| 6 months||1/2||Liver–kidney||1 Liver–kidney|
|Infection||Proven||Strongyloides|| 3 months||1/3||Kidney||1 Kidney|
| ||C. albicans||4.5 months||2/3||Kidney × 2||1 Kidney|
| ||Tuberculosis|| 7 weeks||2/3||Kidney × 2||1 Kidney|
| ||HIV + HCV|| 10 months||4/4||Heart kidney × 2 Liver||1 Liver|
|Probable||Tuberculosis|| 3 months||1/5||Lung||0|
| ||Tuberculosis2|| 3 months||1/6||Lung||1 Lung|
|Possible||Legionella|| 12 days||1/6||Lung||0|
| ||Syphilis|| 4 days|| 0/33||–||0|
| ||C. albicans|| 6 weeks||1/4||Heart||1 Heart|
| ||Schistosomiasis|| 1 day|| 0/64||–||0|
| ||Histoplasmosis|| 4 months||1/4||Liver||0|
| ||Histoplasmosis|| 11 months||1/1||Liver||0|
Of the 2007 infectious diseases reports, five were ultimately determined to be proven, two were deemed probable based on available information and six were deemed possible (Table 6). In all proven cases, the pathogen was clearly documented in both the donor and at least one of the recipients. In one of the probable TB transmissions, the infection was diagnosed in the transplanted organ shortly after transplantation and typing suggests that the TB may have originated from the donor. In the second probable TB transmission, the donor was recognized, as part of a look-back investigation, to have been diagnosed but not treated for latent TB. In both cases, predonation cultures were not available in the donor. In many of the cases of possible transmissions, all or most of the recipients received antimicrobial therapy directed at the detected pathogen before testing could be completed. As a result, infection could not be documented in more than one recipient. In the case of the syphilis and schistosomiasis cases, donor testing suggested active infection and early therapy was provided; none of the recipients had documented infection but the evidence available to the Committee suggested that transmission could have occurred without antimicrobial intervention. There were seven deaths, and all events with proven transmission of a donor-derived infection had at least one fatality. Death occurred in 40% of those recipients with documented infection, while 12% of all recipients of organs with proven, probable or possible donor-derived infection transmission died.
In 2007, definitive transmission of a donor-derived tumor could be documented in seven recipients from four donors; in another event, a recipient developed melanoma in the transplanted organ (liver) 6 months after transplant but the Committee was unable to determine if the tumor was of donor or recipient origin. Transmission occurred in 57% of the recipients of proven or possible donor-derived malignancy events in 2007. There were five deaths attributable to donor-derived malignancy transmissions. This represents deaths in 40% of reported donor-derived malignancy events and 63% of recipients with confirmed transmission of malignancy.
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Over the past 3 years, the number of potential donor-derived infections and malignancies reported to the OPTN has increased from 7 to 97 per year. Transmission of infection was documented in 24% of reports while malignancy transmission was documented in 22% of reports. When transmission occurred, there was substantial morbidity and mortality among affected recipients. Donor-derived disease transmission, though, remains a rarely recognized complication of solid organ transplantation with a reported incidence of 0.96% of deceased donor donations in 2007; documented incidence has increased every year since reporting has been required. Most of this increase is likely the result of improved recognition and the development of a formalized reporting process. The true incidence is not known but will be clarified over time through enhanced reporting by OPOs and transplant centers and improved evaluation of cases by DTAC. When transmission occurred, significant morbidity and mortality, around 40%, was observed. A better understanding of these risks will be important to better inform patients and to provide advice on how to minimize transmissions in the future.
The work of the DTAC allows the OPTN to better understand the risks associated with infection and malignancy transmission from a donor to transplant recipients. Although reports of potential transmissions of HIV, HCV and HBV were not uncommon, most of these reports were attributable to false positive laboratory testing, typically stemming from additional testing required for tissue donated from the same donor. Similarly, several of the Chagas and toxoplasmosis events represented positive donor serology without evidence of transmission to the recipients. Many of the reported malignancies, especially renal cell carcinomas, were of limited disease in the donors and do not appear to have been readily transmitted to the recipients (16); follow-up on these malignancy cases is still ongoing and a more comprehensive review of this issue is needed. As more data are accrued, better inferences into the relationship between tumor stage and risk of transmission may be possible. From such data, it may be possible, in the future, to identify situations where risk of malignancy transmission from donor to recipient is low and may be used more consistently and safely. A working group has recently been formed to review the available data and provide recommendations along these lines.
These data must be interpreted with great caution because of the intrinsic limitations involved in the OPTN reporting process. First, there is underreporting of events. Reporting of potential donor-derived disease transmission events to the OPTN is a subjective process. Providers may have varying interpretations of the clinical scenarios that present themselves in transplant recipients. If the clinician does not consider the possibility that an infection or malignancy is donor-derived, a report from the transplanting institution will not be submitted. Although reporting is required by OPTN policy, it is likely that events are underreported. There are increasing numbers of events reported each year, most likely due to increased awareness of the responsibility of OPTN members to report these cases, rather than a true increase in the underlying incidence. Additionally, we are aware of cases that have been published in the literature but have not been reported to UNOS (17–19). Second, there may be significant delays between the transmission event and reporting to the OPTN. Several events were reported well after the potential transmission had occurred allowing for limited input from DTAC in the evaluation and management of events. There are also challenges to recognizing donor-derived disease transmissions. If organs from the same donor are transplanted into recipients at different centers, clinical features seen in all or most of the recipients may not be recognized as occurring because of limited communications between centers post transplant. In most events, discussion between centers spontaneously occurred when a patient was significantly ill or had expired.
Third, there is no standardized cluster analysis of recipient outcomes to determine if similar disease occurred in recipients of organs from the same recipient—it is currently possible to report two or more recipients as having the same rare malignancy without linking these findings in the already established data bases.
Fourth, the follow-up on these events is very limited. Testing recommendations provided by the DTAC during the course of determining whether transmission has occurred is entirely voluntary; although the Committee often suggests additional testing that may assist in proving or disproving the possibility of donor-derived transmission, follow through with additional testing is highly variable. Similarly, detailed follow-up information may be limited, particularly in events with the threat of litigation. Finally, by current OPTN policy, the DTAC can only obtain direct follow-up specific to the event reported in the Patient Safety system through 45 days after the first report. For many potential donor-derived diseases, particularly malignancies, the ability to identify potential transmission at 45 days is limited. Longer-term detailed follow-up to the DTAC is clearly needed to document potential transmission as well as recipient outcomes.
Fifth, the evaluation of cases and review of data by DTAC has been evolving over the past several years. Although there was informal discussion of cases reported during 2005 and 2006, DTAC met in person for the first time in 2007 and developed a more formalized process for reviewing cases. During this meeting, the Committee reviewed the details of the 2007 cases in far greater detail than was done in previous years. As a result, the Committee feels that it can more accurately proscribe the likelihood of transmission of cases from 2007 than those reported earlier. We present the unaudited cases reported during the first 2 years both because reporting was required during the first 2 years and also to give a clearer sense of the types of reports made to the group.
The Committee is working to address some of these limitations. First, we are attempting to educate the transplant community about the reported donor-derived infections and to encourage enhanced identification and reporting of events. We are accomplishing this through presentation at national and international scientific meetings, presentation at the OPTN/UNOS regional meetings, and publications, such as this one. Second, we are going to attempt to utilize existing data bases to better identify disease transmissions. We are crafting a data request to look at mortality and malignancy data of all recipients from the donors that have had reports of potential disease transmission. Hopefully, this will allow us to identify information that comes in beyond the day 45 report, particularly in the setting of malignancies, or transmissions that are not recognized locally. Additionally, we are looking into the feasibility of attempting to do a cluster analysis of all donor and recipient data in the OPTN and Scientific Registry of Transplant Recipients (SRTR) data bases to identify unreported or unidentified transmissions. Third, the Committee is continuing to revise how we collect, manage and evaluate the data that is provided to us. Hopefully, this will refine our results as we move forward. Fourth, we are in the process of considering recommending revisions to current OPTN policy to streamline and enhance the current reporting of potential and proven transmissions.
This represents the first formal DTAC report of potential disease transmission cases reported to the OPTN. The DTAC is refining the process by which collection and review of the available data enable a better understanding of the changing trends in donor-derived disease transmission. Additionally, there are similar efforts to identify potential donor-derived infections in Europe, Australia and New Zealand that may further our ability to more accurately estimate the true risk of donor-disease transmission through transplantation. Despite the limitations of the current data, it helps to advance our understanding of donor-derived disease transmission. Without an OPTN system of reporting and review in place similar to what is currently in use, it would not be possible to catalogue transmission events and potential near misses to allow changes in policy and practice to improve patient safety. Clinicians should be constantly aware of the possibility of donor-derived disease. Enhanced communications between clinicians caring for transplant recipients with infections and malignancies is crucial and may lead to the earlier identification of transmission events and reduced morbidity and mortality through earlier intervention. Similarly, early involvement of the local OPO to facilitate communication and reporting of potential events is essential. With enhanced recognition of donor-derived disease transmission, increased reporting to the OPTN and review by the DTAC should occur. As more is learned from reviewing these transmission events, the DTAC can advocate for modifications to OPTN policies and develop practices to reduce the likelihood of these transmissions. As a public health issue the dominant risk is that 6000 patients a year die waiting on the list. Although the disease transmission rate is comparatively small, this OPTN effort in DTAC is critical for minimizing the chances that disease transmission will negate the otherwise lifesaving potential of each transplanted organ.
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DTAC wishes to thank Dr. Jay Fishman who was instrumental in the establishment of the Committee. His strong advocacy of these important issues is continuing to help transplant patients.
The findings were presented at the OPTN/UNOS Board Meeting (February 21, 2008), at the American Transplant Congress (Toronto, Canada, abstract LB2), and at the XXII International Congress of the Transplantation Society (Sydney, Australia, abstract 635). Some of the data from this paper was also presented at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America (Washington, DC).
This work was supported wholly or in part by Health Resources and Services Administration contract 234-2005-370011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.