Editorial Comment: The Other Consequences of CMV Infection

The Editors of Transplantation are gratified to present to our readers this supplement to Transplantation entitled, “Beyond Prevention of Cytomegalovirus Infection”. The material contained in this symposium is derived from papers presented at a satellite symposium held in conjunction with the XXth International Congress of the Transplantation Society in Vienna, Austria. In the first presentation, guest editor Richard B. Freeman of Tufts University notes that CMV is the most common viral infection after solid organ transplantation (SOT) with both direct and indirect effects in transplant recipients. Direct effects include clinical syndromes caused by direct tissue invasion and indirect effects include increased risk of additional opportunistic infection, graft rejection, and possibly a number of other complications as well as increased patient mortality. CMV disease has been associated with development of atherosclerosis and has been proposed as a risk factor for cardiac complications in renal transplant patients, as well as a cause for coronary vasculopathy in cardiac transplant recipients. In addition, biliary complications have been shown to be significantly more common among liver transplant patients with CMV antigenemia. He notes that a number of studies have demonstrated the benefits of antiviral prophylaxis in reducing the incidence of CMV disease post-SOT. Optimal strategies for the prevention and treatment of CMV infection and disease in SOT patients are still evolving. Freeman argues that implementation of effective prophylaxis strategies should permit identification not only of direct disease incidence/ reduction but also of amelioration of indirect complications as well. In the first manuscript, Hartmann, Sagedal, and Hjelmesaeth of Rikshospitalet University Hospital, Oslo, Norway examine the natural course of CMV infection and disease in a series of 477 consecutive renal transplant recipients (397 first transplants and 80 retransplants) who were surveyed continuously for CMV infection (defined as pp 65 antigenemia) and CMV disease (antigenemia and clinical syndromes) while no CMV prophylaxis or preemptive therapy was given. They examined the effects of CMV infection and disease on renal allograft rejection, long-term recipient and graft survival, and new onset diabetes. CMV infection and disease were found to be independent risk factors for allograft rejection and new onset diabetes mellitus within 100 days posttransplantation, and for recipient mortality and increased graft loss beyond 100 days posttransplantation. These authors emphasized that additional studies are needed to determine whether CMV prophylaxis or preemptive therapy may be of benefit in preventing these complications. Mark Pescovitz of Indiana University presents a summary of current studies in the literature which demonstrate the benefits of CMV prophylaxis in reducing the risks of indirect effects of CMV infection: acute and chronic allograft rejection, graft failure, patient mortality, cardiac complications and atherosclerosis, and posttransplant lymphoproliferative disorder, in SOT recipients. He provides data to suggest that early acute graft rejection is reduced in patients prophylaxed with acyclovir or gancyclovir suggesting among other things that antiviral medication can act as an immunosuppressive agent during the early posttransplant period. Additional data in the literature has suggested that development of early CMV disease is associated with increased chronic graft rejection and graft loss. Patients whose CMV disease was treated while on mycophenolate mofetil (MMF) therapy appeared to be protected from the long-term consequences of CMV disease on graft survival; a synergistic efficacy between the two drugs has been postulated. Similarly, CMV infection after liver transplantation for hepatitis C virus (HCV)-induced cirrhosis suggested an association between CMV infection and graft failure, i.e. graft failure was significantly more common in patients who developed CMV posttransplant as compared with those who did not. The results suggest CMV prophylaxis may be beneficial in patients undergoing liver transplantation from HCV infection. With regard to cardiac complications and antigenemia, Pescovitz cites two large retrospective studies suggesting that CMV infection increased the risks of death from cardiovascular causes and/or increased the risks of cardiac complications after kidney transplantation; both studies imply a role of CMV infection in pathology of coronary heart disease. Furthermore in a randomized placebo-controlled study of heart transplant recipients, the incidence of coronary artery disease (CAD) was lower in patients who received CMV prophylaxis with gancyclovir than in those who did not receive CMV prophylaxis. Pescovitz also provides interesting data to show that CMV prophylaxis with gancyclovir in liver and kidney allograft recipients reduced the mortality from all causes versus that seen without prophylaxis. Finally, he identifies additional suggestive data that CMV prophylaxis with gancyclovir or acyclovir/gancyclovir reduced the risk of posttransplant lymphoproliferative disease (PTLD). Atul Hunar of Toronto General Hospital summarizes the available data on reactivation of various viruses in solid organ transplant recipients who received concurrent anti-CMV prophylaxis. The data was derived from a randomized, double-blind, international clinical trial conducted at 57 Centers in North America, Europe, and Australia/New Zealand involving 364 patients. The study demonstrated the efficacy and safety of oral gancyclovir or valganciclovir in preventing CMV disease in CMV D+/R-SOT donor-recipient combinations; recipients received oral gancyclovir (1000 mg/3× day) or valganciclovir (900 mg/1× day) for 100 days posttransplantation. A series of substudies was conducted in 263 patients to analyze the reactivation of various viruses in SOT patients receiving anti-CMV viral prophylaxis. They investigated the incidence and clinical relevance of reactivation of human herpes viruses 6, 7, 8, varicella zoster virus, Epstein-Barr virus, Polyomavirus (BK and JC), and adenovirus, and the effect of CMV prophylaxis on clinical and subclinical non-CMV viral infections in SOT patients. The data generated show that viremia caused by a number of viruses is surprisingly common posttransplantation; most of these infections likely represent reactivation of endogenous latent virus. In addition, although infection or active viral replication was common in this cohort of SOT patients, symptomatic disease due to these viruses was uncommon and the clinical sequelae of viremia were unclear or not apparent. The author speculates that CMV prophylaxis may have modified the natural history of some of these non-CMV viral infections. These symposium papers present suggestive, at times provocative, but as yet unsubstantiated data that prophylactic anti-CMV viral therapy can modify not only the direct viral infection effects but also the indirect effects of CMV infection/disease as well. Clearly, additional well-defined, randomized, controlled studies directed at specific questions are required to confirm or deny these impressions. This supplement is published to provide information which we think may be of interest and use to our readership. The Editors of Transplantation wish to emphasize that these papers have not been subjected to the standard, peer review process used for other articles published in Transplantation. Rather the symposium articles have undergone a modified editorial review process in which every effort has been made to identify and remove errors and bias on the part of the authors and/or sponsors. Finally, publication of this symposium should not be interpreted as an endorsement by Transplantation of any ideas or products of the authors and/or sponsors. We welcome your thoughts and comments. Anthony P. Monaco Peter J. Morris

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