Poorer Outcomes for Recipients of Heart Allografts From HCV-Positive Donors: Title and subTitle BreakOpening 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.¹ 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.^{2 - 3} 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.^{4 - 6} 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,^{4 - 6} whereas CMV infection increases the incidence of Epstein-Barr virus–associated lymphoproliferative disease by a factor of 7 to 10.^{5 - 12}

Third, perhaps the most important linkage is that in which viruses and allograft injury interact. The observation by Gasink and colleagues¹³ 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 HCV-positive 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^{4 - 5} 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.^{4 - 5} 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.^{4 ,6 - 9}

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 indirect effects produced by mediators released in response to the processes listed above. Direct injury is associated with an HCV-induced effect on innate, humoral, and cell-mediated immunity. The virus evades the host immune response and induces cell injury.¹¹ The effect of HCV on cell-mediated immunity is most vital in the pathogenesis of the disease, allowing the virus to alter cytokine kinetics, particularly interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α), without altering the cytotoxic effect of CD8-positive T cells. Cell-mediated immunity is susceptible to immunosuppressants, compounding the negative effects of HCV on the recipient.

Three types of indirect effects have been defined in organ transplant recipients and are thought to be due to the release of the cytokines and chemokines in response to rejection, infection, and other conditions. The pattern of this mediator response appears to be similar, whether viral infection or noninfectious processes are involved. Hepatitis C virus contributes to the net state of immunosuppression, thus increasing the risk of secondary infection. A considerable body of evidence in both humans and animal models indicates that systemic viral infection is associated with the release of the same array of cytokines that are in traditional rejection and may play a contributing role in the pathogenesis of certain forms of malignancy.^{2 ,4 ,7 - 10}

It is hypothesized that viral load is a significant factor in HCV-mediated effects. Hepatitis C viral levels increase considerably after all organ transplants, and by the end of the first year are 10- to 20-fold greater than pretransplant.^{4 ,11 ,14} There has been an association between HCV viremia at 4 months after liver and kidney transplants, in addition to the heart, and histological activity suggestive of direct cytopathic injury. The viremia can be further worsened by administration of pulse-dose corticosteroids, which can increase viral levels further by 4- to 100-fold.^{4 ,11 ,14 - 16}

The question that remains is how patients should be managed in the face of a potential organ donor who is HCV positive. The results of the study by Gasink et al,¹³ demonstrating a survival disadvantage among heart transplant recipients who had HCV-positive donors, provide support for the position that transplanting hearts from HCV-positive donors should be avoided if possible. Studies in other organ recipients suggest similar results.^{4 ,14 - 15} Exceptions could be made for critically ill patients who will not survive without a transplant.

Moreover, the presence of HCV in the possible recipient does not prevent superinfection with transplantation. For those patients, 3 additional steps should be taken: eliminate other processes (eg, CMV infection) that could modulate the course of the patient and the allograft; consider a trial of the most effective regimen currently available for transplant patients (pegylated interferon in combination with ribavirin); and eliminate factors that promote HCV. These include high-dose immunosuppression; avoidance of HCV genotype 1b, which has been linked with higher viral loads, a more accelerated course, and a poorer response to interferon-based therapy^{4 ,9 - 10} ; the presence of quasispecies of the virus; iron overload; and too close matching of donor and recipient major histocompatability complex class II antigens. Currently, patients are not treated for HCV after cardiac transplantation because of the perceived risk that interferon may induce graft rejection. This has a dual effect of graft dysfunction and further increasing HCV viremia and its cytotoxic effect by pulse steroids and altered cytokine profiles. The safety of pegylated interferon and ribavirin has not been adequately assessed after heart transplantation, which is necessary if HCV-positive marginal donors are to be considered. The effectiveness of steroid-free protocols in preventing rejection and HCV disease should also be investigated. Stratification strategies based on these associations will be important in evaluating potential therapy, not only for heart transplant recipients, but also for those receiving other organs.^{9 ,15}