Donor-Derived Infection: Old Problem, New Solutions? (2008)

Reports of the transmission of infection to organ transplantation recipients remain uncommon but occur with sufficient frequency to suggest that current approaches to screening of donors are inadequate. Recent transmissions of unusual viral infections have illustrated the vulnerability of immunosuppressed recipients to infections due to organisms of modest virulence for normal individuals. This theme was sustained in a recent report by Palacios et al. from Australia of the transmission of a novel arenavirus related to lymphocytic choriomeningitis virus (LCMV) to three organ recipients from a common donor (1Palacios G Druce J Du L et al.A new arenavirus in a cluster of fatal transplant-associated diseases.N Engl J Med. 2008; 358: 991-998Crossref PubMed Scopus (563) Google Scholar). The donor was a 57-year-old male who died from cerebral hemorrhage 10 days after returning from a trip to rural Yugoslavia. Liver and kidneys were transplanted into three recipients respectively. All three recipients developed a febrile illness accompanied by encephalopathy and varying degrees of organ involvement. Extensive microbiological work-up for suspected pathogens was negative and all three recipients died. Previous reports of two similar clusters, in which seven out of eight recipients died from LCMV, were notable for the lack of symptoms in the deceased donor (who died of acute CNS hemorrhage) and the inability to detect LCMV in tissues from the organ donor even using specific primers derived from the recipients’ viral strain (2Fischer SA Graham MB Kuehnert MJ et al.LCMV in Transplant Recipients Investigation Team. Transmission of lymphocytic choriomeningitis virus by organ transplantation.N Engl J Med. 2006; 354: 2235-2249Crossref PubMed Scopus (431) Google Scholar). Other recent clusters have been due to rabies, West Nile virus (WNV) and HIV. What can be done to minimize the risk of such events? First, transplant physicians must consider donor-derived infection in the differential diagnosis of posttransplant syndromes (3Fishman JA Infection in solid-organ transplant recipients.N Engl J Med. 2007; 357: 2601-2614Crossref PubMed Scopus (1423) Google Scholar). Often the only clue is the presence of an unusual symptom complex presenting in multiple recipients of organs from a common donor. However, since the recipients of organs from a single deceased donor generally receive care at multiple transplant centers, recognition of shared syndromes is often impossible. One approach to enhancing communication is the Transplant Transmission Sentinel Network (TTSN) a web-based system under development by UNOS under a contract from the Centers for Disease Control and Prevention (CDC). When completed, the goal of TTSN is to provide real-time tracking for organs and tissues for all US donors and recipients. Infections, cancers and shared recipient symptom complexes can be reported and tracked, and public health investigations initiated in a timely fashion. Potentially, early recognition will allow earlier therapeutic intervention. In addition, transplant centers must have the ability to identify unusual pathogens. Molecular and antigen –detection-based diagnostic assays have increased the likelihood of specific diagnoses (4Wilck M Fishman JA The challenges of infection in transplantation: Donor-derived infections.Curr Opin Organ Transplant. 2005; 10: 301-306Crossref Scopus (19) Google Scholar,5Relman DA New technologies, human-microbe interactions, and the search for previously unrecognized pathogens.J Infect Dis. 2002; 186: S254-S258Crossref PubMed Scopus (99) Google Scholar). Molecular techniques exist that detect rare or unknown genetic or protein sequences, as may be the case in donor-derived infections, by subtracting out human ‘background’ and amplifying and sequencing the remaining sequences based on phylogeny (e.g. viral elements) or homology (i.e. with known pathogens) and compared with genetic data bases (e.g. BLAST). Common forms of this approach include differential display and representational difference analysis which have been used to identify the sequences of novel pathogens that are ‘out of place’ in infected tissues. Palacios et al. have used the innovative approach of ‘unbiased high-throughput sequencing’ to identify pathogen-specific nucleic acid sequences from clinical samples (1Palacios G Druce J Du L et al.A new arenavirus in a cluster of fatal transplant-associated diseases.N Engl J Med. 2008; 358: 991-998Crossref PubMed Scopus (563) Google Scholar). Reverse transcribed-RNA preparations were amplified using random primers and sequenced. Unique, nonhuman sequences were assembled into contiguous sequences and compared with nucleic acid databases. Their efforts detected a set of arenaviruses similar to LCMV. However, these approaches, while essential to the recognition of new human pathogens, are time consuming, and laborious and impractical for organ donor screening. Even techniques used to screen for large numbers of known pathogens such as multiplex PCR exceed technology that is available at most clinical laboratories. Bearing in mind that donor screening must occur in a timely fashion to allow the use of organs for transplantation, it is clear that we need new assays and new platforms. This technology exists in various forms, but has not been cost-effective for development on the part of the assay companies. How do we approach change in organ donor screening practices? At present, careful clinical histories are helpful. However, many potential exposures are either too common or too nonspecific to allow appropriate decision-making regarding risk of transmission. In some instances of reported transmission, no clear exposure could be identified even with retrospective investigation. For some pathogens such as HIV, the veracity of exposure history may be suspect. The best alternative is laboratory testing of donors for a wider array of pathogens. This must be performed in a rapid and cost-effective manner. The selection of the ‘list’ of pathogens for screening of organ donors might be shaped by a series of specific questions: (1) is the pathogen prevalence sufficiently high in the in the general population for the positive predictive value of the screening test to be useful?; (2) is there evidence that the pathogen can be transmitted by organ donation?; (3) does transmission result in significant morbidity and mortality?; and (4) is there a reliable and logistically applicable test available for screening? For the majority of recent transmission events, including LCMV, the newly reported arenaviruses, and rabies, all of the above criteria are not fulfilled. Therefore although it is clear that such pathogens can be transmitted by organ transplantation and lead to serious morbidity and mortality, there are no currently available diagnostic tests for these pathogens that could be easily applied to donor screening. In the initial series, even knowing that LCMV was a causative agent, the virus was detected in multiple recipients and a pet hamster but was never detectable in donor tissues (2Fischer SA Graham MB Kuehnert MJ et al.LCMV in Transplant Recipients Investigation Team. Transmission of lymphocytic choriomeningitis virus by organ transplantation.N Engl J Med. 2006; 354: 2235-2249Crossref PubMed Scopus (431) Google Scholar). This reflects the low level of viremia in normal donors when compared with the amplification of infection in the immunosuppressed recipients. Thus, given the level of viremia and the low frequency of these agents in the general population, it is unlikely that a sufficiently sensitive and specific screening test could be developed and applied in the short term. Even for a pathogen such as WNV where disease outbreaks may be associated with high prevalence in the general population, and for which screening tests have been very successfully applied to blood products, their use in transplantation remains controversial. One medical decision analysis suggested that screening for WNV may increase overall wait-list mortality due to false-positive tests and organs being discarded unnecessarily (6Kiberd BA Forward K Screening for West Nile virus in organ transplantation: A medical decision analysis.Am J Transplant. 2004; 4: 1296-1301Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). So is the situation hopeless? First, it should be emphasized that these events continue to be very uncommon and that current screening practices have a remarkable track record for maintaining safety in transplantation, considering the number of potential organ and tissue donors that are screened each year. Second, we should realize that the screening of organs for pathogens is about risk mitigation and not about risk elimination. It is unlikely we will ever be able to completely eliminate the risk of disease transmission associated with transplantation. Such a goal is unrealistic with present technology. However there is room to improve donor screening and the detection of such events when they occur, to improve communication regarding transmission events, and to deploy therapies and public health investigations more quickly than is possible at present. The process of donor screening must continue to evolve with our knowledge about the ever-changing field of infectious diseases.