Donor-Derived Transmission Events in 2013: A Report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee : Transplantation

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Donor-Derived Transmission Events in 2013

A Report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee

Green, Michael1; Covington, Shandie2; Taranto, Sarah2; Wolfe, Cameron3; Bell, Walter4; Biggins, Scott W.5; Conti, David6; DeStefano, G. David7; Dominguez, Edward8; Ennis, Donna9; Gross, Thomas10; Klassen-Fischer, Mary11; Kotton, Camille12; LaPointe-Rudow, Dianne13; Law, Yuk14; Ludrosky, Kristen15; Menegus, Marilyn16; Morris, Michele I.17; Nalesnik, Michael A.18; Pavlakis, Martha19; Pruett, Timothy20; Sifri, Costi21; Kaul, Daniel22

Author Information
Transplantation 99(2):p 282-287, February 2015. | DOI: 10.1097/TP.0000000000000584
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The United Network for Organ Sharing (UNOS) is a private, non-profit organization that manages the United States’ organ transplant system under the Organ Procurement Transplant Network (OPTN) contract with Health Resource and Service Administration. Since 2005, OPTN policy has required reporting of all unanticipated potential donor-derived transmission events (PDDTE) in support of efforts to track, understand, and learn from donor-derived disease transmission events in the United States.1 This work was initially carried out by UNOS staff and the Disease Transmission Advisory Group, a subcommittee of the OPTN’s Operations and Safety Committee. In 2008, the OPTN expanded this effort through the formation of the ad hoc Disease Transmission Advisory Committee (DTAC).2 Since that time, the DTAC has worked to learn from this experience to enhance the transplant community’s understanding of donor derived disease and continually refine OPTN policies requiring reporting of PDDTE and communication between organ procurement organizations (OPOs) and transplant centers. As importantly, the DTAC built the infrastructure to effectively and reproducibly evaluate individual cases and learn from its growing aggregate experience.1,3 In 2012, the DTAC implemented 2 major enhancements to these processes: the formalization of an algorithm for the reproducible classification of cases and the expansion of assessment from single “donor transmission events” to characterization of each potentially exposed recipient from a reported organ donor. This report provides a description of these new processes and summarizes our assessment of PDDTE reported to the OPTN made using these enhancements in 2013.

METHODS

The OPTN policy requires reporting of unexpected PDDTE to its Improving Patient Safety portal (housed within UNetSM, the national computer system used to allocate organs for transplant) by either transplant hospitals or the OPOs.4 Potential transmission events are initially screened by UNOS staff before undergoing formal review by the full DTAC. A growing number of submitted reports undergo preliminary review by the DTAC leadership (chairperson, co-chairperson, transplant oncology and/or pathology) in an effort to identify reports that do not require full committee review. The rationale for not sending a report out to the full committee could include: duplicate reporting (an event reported by host OPO, and one or more of the recipient transplant hospitals); incorrect reporting (reporting a potential patient safety situation or living donor adverse event into the wrong area of the Improving Patient Safety Portal); expected transmission events (where donor information is known before acceptance of organ and transplant, e.g., accepting a cytomegalovirus positive organ for a CMV negative recipient and providing prophylaxis to prevent infection). In addition, the DTAC leadership also triaged reports if any of the following were true: 1) report came from the donor cultures and no recipient disease was noted; 2) organism isolated from lung only, lungs were not transplanted, and for example, Mycobacterium tuberculosis, organism would not be expected to cause disseminated disease; 3) organism isolated from lung only, lungs were used but organism typically nonpathogenic or covered by routine surgical prophylaxis, for example, oral Streptococci; (4) organism from urine only and kidneys not used; 5) organism from urine only and would be expected to be covered by routine post-surgical prophylaxis; 6) blood culture with organism that is typically considered a contaminant, especially if only recovered from 1 of 2 bottles (e.g., coagulase negative staphylococci, bacillus species). The DTAC does track PDDTE that are submitted but not sent to the committee but these triaged reports are not included in our aggregate database or used for subsequent analyses.

Cases selected for full review were first distributed to the committee via secure email after initial data collection and redaction of all OPO, transplant hospital, and patient identifiers by UNOS staff. Committee members had access to detailed redacted documentation on a secure website. Members of the committee frequently provided additional queries to staff in response to case descriptions and associated supportive data in an effort to clarify the eventual assessment of PDDTE. The UNOS staff facilitated posing these questions to the appropriate sources and presenting responses back to the DTAC via email discussion. Forty-five–day follow-up was obtained from the responsible transplant centers for all potentially exposed recipients. Each case was comprehensively reviewed by 2 committee members who generated and presented their recommendations to the full DTAC for each PDDTE during regularly scheduled teleconferences. Of note, representation from the Office of Blood, Organs and other Tissue of the Centers for Disease Control and Prevention (CDC) serve as ex officio members of the DTAC. For some PDDTE involving diseases of interest (including but not limited to diseases requiring national reporting), the CDC chose to take the lead in the case investigation. However, committee assessment procedures were identical for both DTAC and CDC led case investigations. Beginning in 2012, an algorithm was introduced to standardize the assessment of the likelihood of donor derived disease transmission. An additional change in DTAC process that same year was that the assessment of likelihood of transmission which was individually determined for every organ recipient for a given donor and the potential event as a whole using this algorithm (Figure 1). The likelihood of transmission was defined as proven, probable, possible, unlikely, excluded, or intervention without disease transmission (IWDT) (typically an antimicrobial)2 for all recipients of a given donor. The overall assessment for a PDDTE was based on the highest level (e.g., proven versus possible) assigned to any of the potentially exposed recipients. Once recipient assessments and an overall assessment are assigned for each PDDTE, this information was recorded in the database. Under rare circumstances, a case may be classified as ‘excluded as of this time’ in the event of recognized long latency periods (e.g. Mycobacterium tuberculosis, certain malignancies). In those cases, staff periodically reviews reports of posttransplant malignancies, graft failures, and deaths provided to the OPTN on standard data collection forms to identify cases needing further committee review.

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FIGURE 1:
Current algorithm for the evaluation of potential donor-derived disease transmission events. For a larger version of this image, please see Figure S1, SDC, https://links.lww.com/TP/B137.

All cases reported during 2013 and reviewed by the DTAC were analyzed, and all PDDTE were considered within the confines of confidential medical peer review. Because of this, the DTAC is not permitted to provide specific details for any given single potential transmission event or to provide details for any disease type where only a single report was received during the year. PDDTE classified as either proven or probable as well as those categorized as unlikely or excluded were combined for the purpose of analysis.

RESULTS

A total of 443 PDDTE reports were submitted to the OPTN Improving Patient Safety Portal in 2013. Of these, 159 were not sent out to the full committee after pre-prescreening by UNOS Staff and DTAC leadership. Approximately one third of these were not reviewed because they were duplicate reports and two-thirds were not sent out for to the full DTAC because they were determined by DTAC leadership to not merit full committee review. The remaining 284 reports were reviewed by the full DTAC. This was a 43% increase from the 198 cases undergoing full committee review during 2012. There has been a steady increase in the number of cases classified by the DTAC each year from 7 in 2005 to the 284 in 2013 (Figure 2) Two hundred three (71%) of the 284 reports involved concern for transmission of infectious pathogens, 65 (23%) malignancies and 16 (6%) for other noninfectious/nonmalignancy potentially transferable diseases (Figure 3). Twenty-four (12%) of the 203 infection-related PDDTE were characterized as being proven/probable, 67 (33%) as IWDT and 91 (45%) as unlikely or excluded, with remaining 21 cases classified as possible. Of 65 malignancy-related PDDTE, 5 (8%) were characterized as being proven/probable, 5 (8%) as IWDT and 52 (80%) as unlikely/excluded.

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FIGURE 2:
Number of potential donor derived disease transmission events reviewed by the DTAC 2006 to 2013.
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FIGURE 3:
Categorization and Outcome of Potential Donor Derived Disease Transmission Events reported to DTAC in 2013.

Malignancy

A summary of the malignancy-associated PDDTE is shown in Table 1. Overall, 5/65 (8%) of the malignancy-associated PDDTE were determined to be proven/probable, affecting 8 recipients and resulting in 2 recipient deaths. Concern for potential transmission of renal cell carcinoma (RCC) accounted for 20/65 (31%) of the total malignancy reports to the DTAC in 2013. However, no proven/ probable transmissions of RCC were documented by the committee. In contrast, concern for transmission of adenocarcinoma accounted for six PDDTE reports, with 2/6 being categorized as proven/probable affecting 2 of 4 exposed recipients and resulting in one death. Of note, while only one of four potential events related to melanoma was felt to have resulted in a proven/probable transmission, all recipients from this donor developed melanoma.

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TABLE 1:
Summary of malignancy-associated PDDTE reports to the OPTN Ad Hoc disease transmission advisory committee in 2013

Infection

Bacteria were the most common infectious pathogen type reviewed by DTAC in 2013, accounting for 99/203 (49%) potential infectious transmissions reports (Table 2) potentially affecting 368 recipients. A proven/probable transmission from the donor was assessed to have occurred in 11/98 (11%) potential events, affecting 12 recipients and resulting in a single death. Concern for Staphylococcus spp. (including methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and Coagulase negative staphylococci) accounted for 32/98 (33%) reports, with 127 potentially impacted recipients. Transmission of MRSA was assessed as proven/probable for two of 10 MRSA-related PDDTE, affecting 3/5 potentially exposed recipients and resulting in one death. Mycobacterium spp. (including MTB, atypical mycobacteria and acid fast bacilli) was the source of concern for 19 PDDTE. However, none of these episodes were felt to be associated with a proven/probable transmission. Gram negative enteric organisms including Escherichia coli, Klebsiella and Enterobacter accounted for ten reports with proven/probable transmission assessed to have occurred from three donors affecting a single recipient in each case with no associated deaths.

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TABLE 2:
Summary of bacteria-associated PDDTE reports to the OPTN Ad Hoc disease transmission advisory committee in 2013

Sixty-two of the 203 (31%) infection-related reports were generated in response to concern for potential viral disease transmission (Table 3). Of the 62 donors, eight (13%) were categorized as being the source of a proven/probable unexpected transmission to 13/28 potentially exposed recipients resulting in one death. PDDTE submitted in response to a concern for potential transmission of hepatitis B virus or hepatitis C virus accounted for 23/62 (37%) viral PDDTE reports. Unexpected Proven/probable transmission of hepatitis B virus was determined to have occurred in a single recipient from each of two donors. No unexpected proven/probable cases of hepatitis C virus transmission were identified in 2013. Concern for unexpected potential transmission of CMV accounted for 6 reports with 2 proven/probable events affecting 4 recipients. Reports of CMV were submitted when both the donor and recipient were CMV seronegative prior to transplant or in response to discordant testing results when donor serologies were repeated by a transplant center. Concern for potential transmission of West Nile Virus (WNV) accounted for 10 reports with one proven/probable transmission from a single donor to three recipients. Six reports of PDDTE due to community respiratory viruses (including Influenza A, Influenza B and parainfluenza) were evaluated resulting in a single proven/probable transmission to two lung recipients from the same donor.

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TABLE 3:
Summary of virus-associated PDDTE reports to the OPTN Ad Hoc disease transmission advisory committee In 2013

Concern for fungal and parasitic infections accounted for 42 (21%) reported infection-related PDTTE. Thirty seven of these were in response to a potential transmission of a fungal pathogen while 5 were due to parasite. Candida was the most frequently reported fungi accounting for 10 reports felt to be associated with a single proven/probable transmission to a single recipient. Coccidioides was the pathogen of concern for 4 PDDTE with no proven/probable transmissions identified. However, 2/13 potentially exposed recipients were considered to have been IWDT. Cryptococcus and Histoplasma collectively accounted for 11 reports but none were associated with a proven/probable transmission. In contrast, concern for Aspergillus accounted for 3 PDDTE with proven/probable transmission to a single recipient from two of the three donors, resulting in one death. Finally, concern for Strongyloides and Trypanosoma cruzi collectively accounted for 5 PDDTE. One of these five donors was assessed to have been responsible for the proven/probable fatal transmission of a parasite to single recipient (Table 4).

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TABLE 4:
Summary of fungus, parasite, and nonmalignancy/noninfection–associated PDDTE reports to the OPTN Ad Hoc disease transmission advisory committee in 2013

Sixteen PDDTE reports were due to concern of transmission of non-infectious and non-malignant processes, including peanut allergies, sarcoidosis, unknown fever and cyanide poisoning, among others. Three of these 16 reports were classified as proven/probable transmissions.

Rates of donor derived disease transmission by category of disease and organ type amongst PDDTE determined to have at least one proven/probable transmission event are shown in Table 5. Amongst proven/probable cases, rates of transmission to all potentially exposed donors varied by category of disease, with malignancies, viruses, bacteria, fungi and parasites leading to transmission in 67%, 46%, 34%, 29% and 17% of all exposed donors, respectively. Similarly, rates of disease transmission from donors with at least one recipient with proven or probable transmission varied by organ with transmission occurring in 80% of exposed lung recipients, 42% of liver recipients, 35% of kidney recipients and 8% heart recipients. At least one recipient was judged to have died in association with a donor derived disease transmission event from each category of disease with infection accounting for 4 of 7 total disease transmission-associated deaths.

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TABLE 5:
Summary of proven/probable PDDTE reports to the OPTN Ad Hoc disease transmission advisory committee In 2013

DISCUSSION

The function of DTAC is to evaluate reports of unexpected PDDTE from organ donors to 1) ascribe likelihood of disease transmission to an organ recipient, 2) provide Board recommendations for policy regarding organ safety and risk assessment and 3) to provide education to the transplant community based upon lessons learned through aggregate OPTN experience (http://optn.transplant.hrsa.gov) (2). OPTN Policy has required reporting of potential transmission events since 2004,2 as a safety provision to promptly communicate risk events to all centers caring for organ recipients from a risk identified in a specific donor. The early DTAC years were characterized by a low volume of reported events with only seven PDDTE reviewed in 2005 and only 164 reports submitted during the first 3 years of the committee existence.1 In contrast, 468 PDDTE were submitted in 2013. 284 (61%) were fully reviewed by the committee. The other cases were screened and triaged by DTAC leadership and staff with no adverse outcomes noted in recipients from these donors. The vast majority of triaged PDDTE were submitted on the basis of culture results reported after donation. It is not clear whether reporting of unexpected PDDTE to the OPTN will stabilize, but continued increases in the number of submitted events will challenge the ability of staff and committee members to accomplish core goals. This report highlights several key changes in our processes which we believe will enhance the ability to optimally draw valid conclusion from this data.

In 2012, the DTAC implemented several changes in PDDTE reviews designed to improve efficiency and reproducibility. First, to expedite decision making, each PDDTE is reviewed by 2 committee members to generate a preliminary assessment using a standardized algorithm. This synopsis and conclusion is presented to the whole committee for final categorization. This structured dialogue has improved processes and should improve reproducibility enhancing validity of the aggregate DTAC experience (despite the continual rotation of members on and off of the committee). The other modification to the DTAC process is the assessment of likelihood of disease transmission for all organ recipients from a given donor in addition to providing an overall assessment for each reported event. The inclusion of the individual assessments allows for a more complete analysis of risk of transmission, allowing for the critical determination of whether all “exposed” recipients are at equal risk of experiencing transmission for a given disease. While this analysis is included in the 2013 report (Table 5), critical conclusions about the risk of disease transmission to individual recipients cannot accurately be drawn until these assessments have been uniformly applied to a larger aggregate experience.

The increased number of reported PDDTE has proven problematic. While it may be that the U.S. transplant community has become more familiar with OPTN reporting requirements, many of the reported cases involve positive donor cultures that were finalized after organs were accepted and transplanted, but with no reported adverse events affecting recipients at the time of the report. Although notification of recipient centers of positive donor cultures may be critical to recipient care, the DTAC was not designed to evaluate all cases with positive donor cultures. The system was originally designed for reports of PDDTE to be driven by concern for disease within a recipient and generally not in response to donor microbiologic or histologic data. Although OPTN policy does require notification of all transplant centers by OPOs of new data that becomes available after acceptance of the organs, it does not require that such cases be reported to the DTAC as PDDTE.2 Efforts are now underway to improve the understanding of what needs to be reported to the OPTN versus to transplant centers alone. Additional efforts are also underway to optimize the efficiency of communication between OPOs and transplant centers to minimize the likelihood of delays in this process.

In 2013, 152 of 284 cases (54%) of PDDTE undergoing full evaluation by the committee were categorized as unlikely/excluded meaning that no evidence of transmission was observed in any recipient despite the absence of use of any disease specific interventions. Seventy-three of 284 (26%) reported PDDTE had 1 or more recipients categorized as IWDT without any recipient experiencing a transmission, suggesting that knowledge of the presence of potential risk can be effectively utilized to protect recipients in many situations. The certainty of attribution is hampered by heterogeneity of case information. In contrast, 32 of 284 (11%) were characterized as proven/probable with 7 deaths associated with these transmissions. In 6 donors and 8 recipients, the submission of the PDDTE report and notification of the transplant centers for other recipients led to interventions that could protect them from the consequences of disease transmission from the donor. This experience demonstrates that the knowledge of the presence of potential risk can be effectively used to help manage recipients in many situations.

It is important to put the risk of donor derived disease transmission into context. Review of the cumulative incidence of PDDTE reported through 2013 involving donors recovered in 2008 to 2012 (Table 6) identifies that only 1.1% of donors were associated with a report of a potential PDDTE to OPTN. Only 0.2% of recovered donors were associated with a proven/probable PDDTE. Similarly, only 0.13% of all recipients transplanted in this period has been assessed as having proven/probable donor transmitted disease, and only 0.03% experienced death in association with a proven/probable donor derived disease transmission. Accordingly, although efforts to enhance our understanding of risk for and potential strategies to avoid development of donor-derived disease are paramount, the actual risk of unexpected donor derived disease transmission amongst transplant recipients remains exceedingly low.

The analysis of any single year of data from the DTAC experience is unlikely to provide evidence to support dramatic improvements in OPTN Policy or enhancement in organ recipient safety. However, this report highlights several recently introduced important improvements in process and analytic methodology. These improvements in process should allow for more robust evaluations of the aggregate DTAC experience providing the opportunity to more fully characterize risk to one or more recipients, improve decision making about the use of donors (potentially increasing the donor pool) and identify potential opportunities for enhancement in the effectiveness of policy, with a consequent goal of improved patient safety.

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TABLE 6:
Cumulative incidence of disease transmission: PDDTE reported 2008 to 2013 involving donors recovered 2008 to 2012

REFERENCES

1. Ison MG, Hager J, Blumberg E, et al. Donor-derived disease transmission events in the United States: data reviewed by the OPTN/UNOS Disease Transmission Advisory Committee. Am J Transplant. 2009; 9: 1929.
2. Ad Hoc Disease Transmission Advisory Committee. Available from http://optn.transplant.hrsa.gov/members/committeesDetail.asp?ID=95. Accessed September 19, 2014.
3. Ison MG, Nalesnik MA. An update on donor-derived disease transmission in organ transplantation. Am J Transplant. 2011; 11: 1123.
4. OPTN Policy 15.4. Available from http://optn.transplant.hrsa.gov/policiesAndBylaws/policies.asp. Accessed September 19, 2014.

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