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Poorer outcomes for recipients of heart allografts from HCV-positive donors: opening the silos.

OVER THE PAST 30 YEARS, ORGAN TRANSPLANTAtion has evolved from an interesting experiment in human immunobiology to the most practical means of rehabilitating patients with end-stage dysfunction. At the same time, the requirement for chronic antirejection therapy, the presence of chronic or relapsing viral infection, and environmental exposures to a variety of opportunistic pathogens, have created a pathophysiological state and set of vulnerabilities rarely seen before. It has been estimated that 75% or more of organ transplant patients will have evidence of microbial replication and invasion in the first year posttransplant. Several principles have emerged from this experience. First, allograft rejection and invasive infection are closely linked, creating the need for a “therapeutic prescription” that has 2 components: an immunosuppressive program to prevent and treat rejection, and an antimicrobial strategy to make this safe. Changes in the immunosuppressive regimen should result in appropriate changes to the antimicrobial program. Second, bidirectional linkages between different processes are the rule, not the exception. Thus, hepatitis C virus (HCV) replication will increase the level of replication of cytomegalovirus (CMV) and vice versa, whereas CMV infection increases the incidence of Epstein-Barr virus–associated lymphoproliferative disease by a factor of 7 to 10. Third, perhaps the most important linkage is that in which viruses and allograft injury interact. The observation by Gasink and colleagues reported in this issue of JAMA that receipt of heart allografts from HCV-seropositive donors is associated with a poorer posttransplant survival is both expected and important. Expected because other viruses, such as CMV, appear to have this effect. Important because the chronic shortage of donors has resulted in attempts to expand the guidelines for accepting allografts, and there has been the hope that organs from HCV-positive donors could be used, particularly for critically ill organ recipients. The results of this study suggest that with current immunosuppressive therapy and antiviral prescription, the use of HCV-positive heart donors is not without hazard, even for HCV-positive recipients; that is, superinfection with HCV occurs, is clinically important, and cannot be generally recommended with current regimens of therapy. The question that emerges is whether special regimens can be developed that would allow the use of such organs with greater safety. In the meantime, the use of hearts from HCVpositive donors should be restricted to the critically ill who would not survive without an immediate transplant; whether such an approach is appropriate for other organs remains to be seen. The traditional view of the pathogenesis of allograft injury is that the triggering of a given pathway results in a unique histopathology. If a different pathway is involved, then the end result is a different histopathology that is recognizable. This so-called silo hypothesis was thought to provide insight into the pathogenesis of different clinical states. Compelling evidence now suggests that this view of pathogenesis is incorrect; rather than separate silos for each process, multiple paths exist that provide entrance into a final common pathway. Thus, such widely disparate processes as ischemia-reperfusion injury, immunologic injury, and certain infections (including HCV, CMV, and presumably other viruses such as human herpesvirus 6 and Epstein-Barr virus) can produce comparable histopathologic findings. The pattern of cytokine, chemokine, and growth factor release associated with each of these processes appears to be quite similar, thus explaining the final common pathway hypothesis. Similarly, the possibility of additive or synergistic effects due to multiple processes occurring simultaneously does not appear unreasonable. In addition, identification and control of these concomitant processes could improve the outcome in certain patients at risk for HCV-mediated processes. The clinical effect of HCV for patients undergoing organ transplantation can be divided into 2 general categories: the direct causation of acute and chronic liver injury, and the