Organ transplantation has added to the quality and. Receiving the Unwanted Gift: Infection Transmission through Organ Transplantation

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1 SURGICAL INFECTIONS Volume 17, Number 3, 2016 ª Mary Ann Liebert, Inc. DOI: /sur Receiving the Unwanted Gift: Infection Transmission through Organ Transplantation Varvara A. Kirchner and Timothy L. Pruett Abstract Background: Infections are common in the general U.S. population, so it is inevitable that some persons with a potentially transmissible disease will become organ donors. There are numerous reports of viral, parasitic, fungal, and bacterial transmission through transplantation. At the same time, immunosuppression increases the risk of infection in organ recipients, so attribution of infectious diseases to the transplanted organ is often difficult. Method: Review of the English-language literature. Results: The Organ Procurement and Transplantation Network states that all potential deceased organ donors must be assessed for conditions that may influence donor acceptance. The infections most often transmitted knowingly to organ recipients are cytomegalovirus and hepatitis C virus. There was a 43% increase in the number of potential donor-derived transmission events between 2012 and 2013, but this affected only 3% of transplants; and the patterns of unexpected infection transmissions have remained fairly constant. The 2013 recognition of a case of raccoon rabies in a kidney recipient brought the risk of untested pathogens back into the general discussion of disease transmission. Also, unexpected transmissions of parasitic infection have resulted in highly visible recipient deaths. Conclusions: Organ transplantation has been an enormous advance in the treatment of chronic diseases, but the risk of unanticipated disease transmission has been gaining attention. The task for the organ donation community is to assess risk of transmission of clinically relevant diseases accurately without substantially diminishing organ availability. Organ transplantation has added to the quality and quantity of life for tens of thousands of individuals, so much so that organ donation is often described as the gift of life. However, there have been multiple reports of an unwanted, unsuspected, and often fatal infection or neoplasm developing in an organ recipient after transplantation. In comparison with the positive benefits of organ transplantation, these are relatively infrequent events but carry enough gravitas that a review of our current knowledge (and gaps therein) is in order. Hindsight has often provided illumination of the putative risks of unanticipated disease transmission. Risks of a Donor Having a Transmissible Disease in the Transplanted Organ Infections are common in the general U.S. population, so it is inevitable that some persons will die with a potentially transmissible disease yet become organ donors. The task of assessing a potential donor is multifaceted, depending on what one is trying to find. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infect the majority of the U.S. adult population and are reactivated in organ recipients. The human immunodeficiency virus (HIV) is present in a small fraction of the population. About 25% of the U.S. population has antibodies to Toxoplasma and probably has the organism in a quiescent form in muscle. Numerous other diseases are seasonal and often asymptomatic (West Nile virus, coccidiodomycosis, and histoplasmosis) such that accounting for the risk of transmissible disease is difficult. There are numerous anecdotal reports of viral, parasitic, fungal, and bacterial transmissions through organ transplantation, as is true of neoplasms, which are not the subject of this review. What is the real risk, how does one perform a risk assessment of using organs from any specific donor, and what does the potential organ recipient need to know? Current Donor Evaluation for Transmissible Diseases The oversight of U.S. organ donation and transplantation is performed by the Organ Procurement and Transplantation Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota. This article was presented at the 33rd Annual Meeting of the Surgical Infection Society, Las Vegas, Nevada, April 12 15,

2 INFECTION TRANSMISSION ORGAN TRANSPLANTATION 319 Network (OPTN), a private corporation (currently called the United Network for Organ Sharing [UNOS]) that functions under a contract awarded by the federal government. The authority for this contract is the National Organ Transplant Act, passed in 1984 and interpreted by the Final Rule in 2000 [1]. The policy of the OPTN states that all patients who might become post-mortem organ donors must be assessed for conditions that may influence donor acceptance by obtaining the donor s history, review of the medical chart, assessment for factors associated with a greater risk of disease transmission, physical examination, and vital signs [2]. For deceased donors, testing should be performed for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, CMV, and EBV, as well as blood and urine cultures [2]. All testing should be done in certified laboratories using U.S. Food and Drug Administration-licensed, -approved, or -cleared tests. Irrespective of the testing results, there is an additional policy that requires a person be informed when offered an organ from a donor identified as high risk by the Public Health Service (PHS) guidelines developed in 1994 [3,4]. In June 2013, the PHS revised these guidelines and redefined donors at increased risk of transmitting HIV, HCV, and HBV [5]. If the donor is identified as high risk, HIV RNA or diagnostic nucleic acid testing or HIV antigen/antibody evaluation is required in addition to standard deceased-donor testing [3]. This policy guides those processes utilized by the organizations that evaluate and retrieve organs in the U.S. When this policy was written, the OPTN had authority over only deceased-donor organ donation and transplantation, but in 2006, its scope was expanded to include live-donor organ donation. The evaluation of a living donor differs somewhat from that of deceased donor. First-person history is obtained, as contrasted with the third-person history that is obtained with deceased donors. Additionally, the time pressure to make a decision for the live donor is less, allowing retesting or use of confirmatory testing for equivocal or newly recognized conditions. However, in live donation, the lengthened time of evaluation permits a donor to acquire a transmissible disease in the time between the initial testing and organ donation, as was the case with an HIV transmission through a live-donor kidney donation [6]. Live donors must be screened for the same pathogens as deceased donors; however, given the possibility of acquisition of infection between testing and donation, the revised OPTN policy states that HIV, HBV, and HCV testing must be performed as close to the donation as possible, but certainly within 28 prior to organ harvest [2]. and provision of a patient safety network to inform centers transplanting other organs from a sentinel donor. The Disease Transmission Advisory Committee (DTAC) was established in 2008 to perform this function. It serves as a portal for information reported by members (organ procurement organizations [OPOs] or transplant centers) about potential disease transmission through transplanted organs. Utilizing the peer review process, the committee ascribes an assessment for the likelihood of disease transmission. Results from the deliberations of the committee are necessarily not complete, and recognition and reporting of transmissible diseases is not uniform across the country. The number of patient safety reports has doubled over the past five years (Fig. 1) [14]. There was a 43% increase in the number of potential donorderived transmission events (PDDTEs) between 2012 and 2013, but this constituted only 3% of all donations (deceased donors being more common than live donors). Although the total number of transmission reports is increasing, attribution of proved/probable (P/P) transmission through transplantation remains low: 17% of transplantations in 2012, 11% in 2013, and 14% in 2014 [7 9]. Low PDDTE numbers could be the result of under-recognition and under-reporting, as most of the surveillance systems are based on the recipient center s ability to recognize a potential donor-derived disease and report it to the oversight system (DTAC in the U.S.) [10]. Reported Infections Transmitted Through Organ Transplantation The national experience differs slightly year by year, but the patterns associated with unexpected infection transmissions have remained fairly constant: (1) Infections caused by pathogens that are not tested for (such as rabies, West Nile virus [WNV], lymphocytic choriomeningitis virus (LCMV), strongyloides, and a variety of fungi); (2) infections from a donor with a pathogen found/recognized at the time of donation, with or without treatment prior to donation (most commonly bacteria) [11]; and (3) testing error or misinterpretation of the meaning of a result. Table 1 summarizes a DTAC report of 2012 activity on infectious and non-malignant PDDTE that was presented at the American Transplant Congress in The complete report described 135 of 166 PDDTEs with 26 donor P/P transmission events to 38 recipients with 10 related deaths. The most frequent pathogens were bacteria, namely, acid-fast bacteria (tuberculosis [TB]), viral hepatitis, protozoa, Surveillance and Recognition of Suspected Transmitted Diseases It is accepted clinical practice that organs are vectors for infection transmission but are still transplanted. The most common infections knowingly transmitted to organ recipients are CMV and HCV (CMV because there is effective prophylaxis and HCV to HCV + recipients, as the outcomes are equivalent to those of patients receiving an HCV - organ). Because these transmissions are expected, they are not tracked through the national biovigilance system. However, the OPTN contract requires risk assessment and attribution of unexpected disease transmissions after organ transplantation FIG. 1. Potential donor-derived transmission events.

3 320 KIRCHNER AND PRUETT Table Infections and Other Non-Malignant Transfers to Organ Recipients Organism type fungi, and then other viruses [7,14]. Interestingly, compared with the DTAC report for 2012, the percent of P/P bacterial transmission events decreased and P/P viral transmission events increased in the 2014 DTAC report, although the total number of bacterial and viral PDDTEs remained the same [7,9]. Bacteria Total no. of donors Most deceased organ donors will have a positive bacterial culture from one of the tested sites during the ante-mortem period. The most common sites for positive cultures are the blood stream and airway; however, urine and abdomen isolates are not infrequent. Most bacterial isolates appear to be irrelevant to subsequent recipient outcome, but occasionally, transmitted bacterial infections have resulted in death. Although the true number of bacteremia cases in the U.S. organ donor population is not reportable, there are literature reports suggesting that about 5% of all deceased donors have unrecognized bacteremia at the time of donation but that few instances are associated with recipient disease [12,13]. Although bacterial transmission from the donor population is rare: Eight donors with P/P bacteria transmission affecting nine recipients from more than 8,000 deceased donors, resulting in three deaths, in 2012) [14]. The national data suggest that gram-negative bacteria account for about 80% of transmissions to recipients, and a significant percentage of these are recognized after ruptured mycotic aneurysms resulting in recipient graft loss or death or both [15]. A particular concern has been with the use of organs from donors with heavily contaminated surgical sites (the open abdomen), as this has been associated with a recognized risk of transmission of infection to an organ recipient [16,17]. Tuberculosis has been well described as being transmitted through organs from donors with active and inactive infections. It is possible that a donor had a subclinical exposure to mycobacterial disease, and information regarding this risk will be slim. In the event of diseased donors, geographic origin, chest radiography, and sputum acid-fast staining may No. of proved/ Probable transmitting donors be the only tests available to assess the risk of disease transmission. The use of quantiferon gold assays has not been found to be reliable or useful in donors dying neurologic deaths. Viruses No. of infected recipients (proved/probable) Bacteria (excluding tuberculosis) Tuberculosis Hepatitis B virus Hepatitis C Virus Strongyloides/ T. cruzi Amoeba or other parasite Coccidioides Respiratory virus Aspergillus Candida Cryptococcus Histoplasma West Nile Virus Other viral Other fungus Other Total No. of related deaths Considerable attention is paid to the risk of transmission of the blood-borne pathogens, HIV, HBV, and HCV through organ donation. All 8,000 + deceased and 5,800 + live donors in 2012 and all 8,500 + deceased and 5,800 live donors in 2014 were tested for these pathogens. During 2012, there were three instances of P/P transmission and a combination of human error/misunderstanding of test results and limitations seemed to be the major contributor to the infrequent disease transmission to organ recipients. In 2014, there were 15 HBV and HCV P/P transmissions, which affected nine recipients without any deaths [7,9]. The impact that the new PHS guidelines and testing requirements will have on organ availability is yet to be defined. The 2013 recognition of a case of raccoon rabies in a kidney recipient [18] brought the risk of untested pathogens back into the general discussion of disease transmission. Other viruses, such as LCMV, WNV, other arenavirus, and flavivirus, have been recognized as uncommon diseases transmitted to organ recipients. Every influenza season, there is concern about transplanting lungs from a donor infected with the causative virus, although to date, there has been no documented influenza transmission. The WNV is found across a broad swathe of the country; there have been several reports of donor-derived infections with this virus resulting in substantial neurologic damage and some deaths [19]. Therefore, the transplant team should be vigilant in the assessment of the potential donor having a viral syndrome associated with headaches, especially in high-risk temporal and geographic regions. Severe acute respiratory syndrome (SARS) was a major concern for a time, but the virus did not appear to penetrate the U.S. donor pool. Although idiosyncratic unexpected transmission of the causative virus has occurred, it remains an infrequently recognized, and as yet unpredictable, event.

4 INFECTION TRANSMISSION ORGAN TRANSPLANTATION 321 Fungi There are a variety of fungi that are regionally associated, coccidioidomycosis in the desert Southwest and Histoplasma in the Ohio River Valley being the best known. The DTAC has recognized a substantial number of coccidioidomycosis transmissions, but few other predictable fungal pathogens. Some desert Southwest transplant teams assume that all local donors have the potential to transmit coccidioidomycosis and use antifungal prophylaxis [20]. One must be cognizant that donors can/could acquire pathogenic fungi and yeast from hospital and environmental conditions, and these organisms are potentially transmissible to organ recipients. Parasites Unexpected transmissions of parasitic infection have resulted in unexpected and highly visible transplant recipient deaths. Strongyloides has come from donors typically from the Caribbean, amoebae from warm, fresh water sources, Chagas disease from individuals spending substantial time in Central America, and toxoplasmosis from just about anyone exposed to infected cats [21 24]. Certainly, not every donor from a specific geographic area will transmit an infection to an organ recipient, but when there is a substantial risk, caution must be exercised. All seronegative heart recipients receiving the organ from a serologically toxoplasmapositive donor should receive prophylactic therapy. Donor with undiagnosed meningoencephalitis The DTAC has observed a common theme in the donors of organs found to have transmitted infections [25]. Many of the uncommon disease transmissions have come with the use of organs from a previously healthy person who subsequently died with an undiagnosed/misdiagnosed neurologic event. The challenge for the treating physicians/intensivists, recovery organizations, and transplant surgeons is to understand the risks attending such a misdiagnoses. There are no data on event frequency when organ donors have suffered neurologic death without a clear pathophysiologic understanding and those organs were used without subsequent disease transmission. However, there are numerous reports of rabies, LCMV, Balamuthia, coccidioidomycosis, and leukemia transmissions to recipients of organs from donors with either undiagnosed or misdiagnosed inflammatory conditions of the meninges or brain [11,24]. Time to Recognition of Transmitted Infections All organ recipients receive immunosuppressive drugs that increase the risk of infections, so attribution of infectious diseases to a transplanted organ often is difficult. The longer that time that transpires after the transplant event, the less likely the organ will be considered as a vector for a transmissible infectious disease. There always will be some unrecognized transmissible infections that are missed/not reported. In a review of the DTAC experience from , the time from the transplant to recognition of the transmitted infection was analyzed [26]. Almost 80% of all transmitted infections were recognized within the first three months after transplantation, and three quarters of these presented within the first 30 after transplantation. The distribution of pathogens is not homogeneous; 23 of 24 Table 2. Days from Transplant to Presentation of Infection Type of infection donor-derived bacterial infections (non-tb) were recognized within 30 d post-transplant, and none has been recognized later than d 45. In the case of fungal infections, 20 of 27 were recognized before 30 d post-transplant, but in several cases, there was a delay past this point. A substantial number of viral disease diagnoses have been made later than 6 mos posttransplant (Table 2). The pattern of early recognition of the infection transmission reported by the DTAC is to be expected. The most dramatic clinical scenarios are from early bacterial transmission manifesting either in septicemia or mycotic aneurysm; acute neurologic deterioration from rapidly progressing WNV, rabies, or LCMV; or the multi-system organ dysfunction associated with certain parasitic and fungal infections. However, there are more indolent infections, when a virus, fungus, or parasite have been relatively well contained in the donor and require time for the clinical disease to be manifested and recognized in the organ recipient. These forms of infection are believed often to be non-donor derived, and in fact, many probably are caused by environmental exposure. However, the practicing clinician must always be cognizant of the possibility of donor-derived infection in transplant recipients. Conclusions >181 Total Viral Bacterial Fungal Mycobacterial Parasitic Total % of all infections Organ transplantation has been an enormous advance in the treatment of chronic diseases. Although the hurdles associated with immunologic organ acceptance, organ preservation, and surgical techniques have been the major clinical focus for decades, the risk to the recipient of unanticipated disease transmission has been gaining more attention. The task for the organ donation community is to assess the risk of transmission of clinically relevant diseases to a potential recipient accurately without substantially diminishing organ availability. The accurate risk assessment for disease transmission by the donor is limited by relatively rudimentary laboratory testing; time constraints, especially relative to the deceased donor assessment; and often-incomplete medical and environmental exposure histories of the donor. In the quest to minimize untoward disease transmissions, one must be cognizant that although the precise number of people being affected may not be known, the numbers of people dying from the progression of their disease is clear. Currently, more than 10,000 people are removed from the transplant waitlist because they either die or become too sick to transplant. The number of disease transmissions pales in comparison. Although organ quality and safety is a key consideration, the availability of organs for transplantation is

5 322 KIRCHNER AND PRUETT turning out to be the major limitation for appropriate care of those with organ failure. Author Disclosure Statement Neither of the authors has any conflicts of interest related to this manuscript. References 1. Organ Procurement and Transplantation Network. Final Rule Available at: optn.transplant.hrsa.gov/governance/ about-the-optn/final-rule/ 2. Organ Procurement and Transplantation Network. Policies Available at: optn.transplant.hrsa.gov/media/1200/ optn_policies.pdf 3. U.S. Centers for Disease Control and Prevention. Guidelines Available at: 4. Organ Procurement and Transplantation Network. Policies Available at: optn.transplant.hrsa.gov/contentdocuments/ Policy_Notice_ pdf 5. Seem DL, Lee I, Umscheid CA, et al. PHS Guideline for reducing human immunodeficiency virus, hepatitis B virus, and hepatitis C virus transmission through organ transplantation. Public Health Rep 2013;128: Echenique IA, Cohen D, Rudow DL, Ison MG. 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Presented at the American Transplant Congress. Abstract B1038 Seattle, WA Am J Transplant 2013;13(suppl 5). Available at: Address correspondence to: Dr. Varvara A. Kirchner Division of Transplantation Department of Surgery University of Minnesota 420 Delaware Street SE, MMC 195 Minneapolis, MN kirc0079@umn.edu