Begin typing your search above and press return to search.
Volume: 5 Issue: 2 December 2007


Alteration of Direct and Indirect Effects of Cytomegalovirus

For recipients of a solid organ transplant, cyto­megalo­virus infection causes many pathological conditions including direct and indirect effects, most notably owing to the potency of the immunosuppressive medications used. Effects attributed to cyto­megalovirus infection include graft rejection, decreased graft and patient survival rates, predisposition to other opportunistic infec­tions, virally mediated malignancies, and various injuries specific to the transplanted organs (eg, accelerated coronary atherosclerosis following heart transplant, bronchiolitis obliterans syndrome in lung transplants, and vanishing bile-duct syndrome in liver allografts). Other indirect effects include post­transplant lymphoproliferative disorders, posttransplant new onset diabetes, and recurrence of hepatitis C virus infection. Direct effects are related to viral burden, whereas indirect effects may be observed even in the presence of low levels of cytomegalovirus replication. Being a function of the interaction between the virus and the host’s immune and inflammatory responses, the underlying indirect effects of viral infection are not completely understood. Whereas it has been shown that cytomegalovirus prophylaxis can decrease the direct and indirect effects of the virus, recent data indicate that pre-emptive therapy has no long-term impact upon the indirect effects. Prevention of cytomegalovirus-related indirect effects might be achieved only with prophylaxis.

Key words : CMV, Organ transplant, Kidney transplant, Prophylaxis, Valganciclovir, Antigenemia

Cytomegalovirus (CMV) is, evolutionarily, a very old virus. It belongs to the Herpesviridae family (subfamily betaherpesvirinae), as does human herpesvirus type 6. CMV is species-specific. Its seroprevalence in the general population ranges from 50% to 100%. Usually CMV primo-infection occurs in children and is often asymptomatic. Subsequently, CMV will remain latent, persisting in epithelial cells, monocytes/ macrophages, endothelial cells, and fibroblasts. When immune surveillance decreases, the virus can become reactivated. The dynamics of CMV replication in humans are high, for example, virus-doubling time is about 1 day (1). CMV replication is under the control of T lymphocytes. Thus, in heart-transplant recipients, those with levels of CMV-specific CD4 T cells detectable during the first month after transplant have significant protection from high mean and peak posttransplant viral loads, acute rejection, and loss of allograft coronary-artery lumen and of whole-vessel area compared with patients who lack this immune response (2). Moreover, losses of lumen and vessel areas both are significantly correlated with the time after transplant at which a CD4 T-cell response is first detected plus the cumulative graft-rejection score (2). Low levels of CMV replication in lung-transplant recipients have been shown to be sufficient to both prime and recruit CMV-specific CD8+ T cells to the major-histo­compatibility-complex–mismatched lung allograft (3). In addition, direct detection of CMV-specific T cells with an effector phenotype in the lung allograft suggests a protective antiviral function (3). In heart- and lung-transplant recipients, protection from CMV after transplant is correlated with an immediate, early, 1-specific CD8 T-cell, but not with a pp65-specific CD8 T-cell, response (4). In some renal-transplant patients, the absence of an anti-CMV T-cell response has been found to correlate with a lack of viral clearance after ganciclovir therapy, even when CMV isolates are not ganciclovir resistant (5).

The virologic diagnosis of CMV replication relies on the presence in blood of pp65 antigenemia or DNAemia. Conversely, RNAemia is less sensitive than pp65 antigenemia or DNAemia in indicating early CMV replication (6). In cases of primo-infection, CMV infection can be associated with the presence of anti-CMV IgM antibodies and eventually, with CMV IgG antibodies (7). Conversely, in the setting of CMV reactivation, CMV serology is of no use.

CMV infection results in direct and indirect effects (8). The direct effects are correlated with the peak of viremia and include the CMV syndrome (ie, a flulike syndrome with sustained fever); mononucleosis syndrome; and tissue-invasive diseases such as hepatitis, myocarditis, pneumopathy, pancreatitis, colitis, retinitis. There is a predilection for the greatest virological-related pathology to occur within the transplanted organ, that is, liver-transplant patients will have hepatitis, and lung-transplant patients have pneumonitis. CMV-infected-tissues show CMV antigens on the cell surfaces, which lead to host-immune responses. The immune response coupled with lysis of the infected cells, results in destruction of infected tissues.

The indirect effects of CMV infection are independent of a high level of CMV viremia and result in part from the effect of the virus on the host’s immune response in the setting of long periods of low-level of CMV replication. This translates into organ allograft injuries (eg, acute or chronic rejections) and suppression of the systemic immune response, thereby leading to opportunistic infections or facilitated replication of viruses such as Epstein- Barr virus (EBV) (9) and hepatitis C virus (HCV) (10). It has been shown that CMV-related indirect effects are decreased or prevented by CMV prophylaxis in animal models (11,12) and in humans (13) but probably not by CMV pre-emptive therapies in humans (13).

In experimental models of kidney, heart, liver, and lung transplants, CMV infection increases the risk of acute and chronic rejections, as well as an inflam­matory response within the allograft (11, 12, 14, 15). These effects might be prevented or reduced by CMV prophylaxis with ganciclovir. In humans, before the era of CMV prophylaxis, Grattan and associates showed that CMV disease in heart-transplant recipients was significantly associated with the development of coronary artery vasculopathy. By 5 years after transplant, coronary artery vasculopathy was present in less than 10% of patients who did not have CMV disease compared with it being present in more than 35% of those who did have CMV disease (16). In lung-transplant patients, those who presented with subclinical infection (ie, asymptomatic DNAaemia or the presence of asymptomatic CMV in fluid following bronchoalveolar lavage) had a greater risk of developing bronchiolitis obliterans 4 years after transplant then did those who had never experienced CMV reactivation (17). CMV prophylaxis can reduce the risk of acute rejection in donor-positive (D+) and in recipient-negative (R-) renal-transplant patients receiving valaciclovir CMV prophylaxis (18), in kidney-pancreas recipients receiving ganciclovir prophylaxis (19), and in D+/R- heart-transplant patients receiving valganciclovir plus CMV hyper­immune globulin prophylaxis (20). Moreover, in heart-transplant recipients, CMV prophylaxis with valganciclovir can reduce the risk of coronary artery vasculopathy as demonstrated by intravascular ultrasound studies (20).

CMV infection is a risk factor for developing de novo diabetes after kidney transplant. Hjelmesaeth and associates found that de novo diabetes was present in 26% of kidney recipients who had asymptomatic CMV infection that had occurred during the first 100 days after transplant compared with only 6% of patients who had no CMV infection (P = .003) (21). However, it has not yet been shown that CMV prophylaxis prevents the development of diabetes after kidney transplant.

CMV infection increases the risk of developing posttransplant lymphoma. Manez and associates conducted a retrospective study in 37 EBV D+/R- liver-transplant recipients (9). Of these 37 patients, 95% developed an EBV primo-infection, and 37% developed posttransplant lymphoma. The only predictive factor that was significantly associated with the development of posttransplant lymphoma was CMV disease (relative risk, 7.3; CI 95%, 2.36-22.6; P = .0006). Moreover, prophylaxis against CMV infection also decreased the number of posttransplant lymphomas. In a multicenter case-control study, the benefits of antiviral treatment with ganciclovir or acyclovir on the development of posttransplant lymphoma in de novo renal-transplant patients were evaluated (22). Antiviral therapy reduced the risk of posttransplant lymphoma by 83%. For each 30-day period of CMV prophylaxis with ganciclovir, the risk of developing posttransplant lymphoma was reduced by 38% (odds ratio, 0.62; CI 95%, 0.38-1). Conversely, acyclovir CMV prophylaxis was less efficient in preventing posttransplant lymphoma (odds ratio, 0.83; CI 95%, 0.59-1.16).

In HCV-positive liver-transplant patients, it has been suggested that the pathogenesis of hepatitis C virus is influenced by CMV (10). However, a recent study showed that liver-transplant recipients with CMV infection, including high-risk D+/R- patients, when followed-up using a pre-emptive therapy approach, had no significant difference in meaningful outcomes (eg, HCV recurrence rates and rejection and survival rates) when compared with patients in whom CMV infection had never developed and who had not received antiviral prophylaxis for CMV (23).

Evidence for CMV-related indirect effects has been reported in prophylaxis studies. In a recent meta-analysis, Kalil and associates reported that in multiorgan-transplant recipients, universal pro­phyl­axis against CMV was associated with a significant decrease in all-cause mortality rates, as well as in CMV-related mortality (24). Another recent meta-analysis showed that compared with a placebo or no prophylaxis, CMV prophylaxis significantly decreased CMV infection, CMV disease, mortality related to CMV disease, and all-cause mortality (25). CMV prophylaxis also might modify the natural posttransplant history of some viruses, such as human herpesviruses 6, 7, and 8; Varicella zoster virus; EBV; polyomavirus; and adenovirus (26). Compared with placebo, prophylaxis against CMV reduced herpes type 1 and 2 infections by 73%, Varicella zoster infection by 35%, and protozoal infections by 69%. However, it did not significantly reduce fungal infections (see Figure 1) (25). With regard to acute rejection, Opelz and associates showed that, in heart-transplant recipients at risk for CMV (ie, D+/R-), patient survival rates were 8% higher in those who received CMV prophylaxis compared with patients who received no prophylaxis (27).

Although CMV prophylaxis has been shown to decrease the direct and indirect effects of CMV, it is not clear whether pre-emptive therapy has an impact on the indirect effects of CMV. Some recent data suggest that it does not (13). A recent study by Radermacher and associates showed that in renal-transplant recipients, compared with pre-emptive ganciclovir therapy, CMV prophylaxis with ganciclovir increased long-term allograft survival after 4 years of transplant by 13.9%. This differs from a recent small study in kidney transplant patients with a short follow-up that demonstrated that use of valganciclovir as a universal prophylaxis was equivalent to pre-emptive therapy with respect to efficacy and costs (28).

In conclusion, CMV is responsible for direct and indirect effects, and prophylaxis can prevent both of these. Conversely, prevention of CMV-related indirect effects is not achievable with pre-emptive therapy.


  1. Emery VC. Progress in understanding cytomegalovirus drug resistance. J Clin Virol. 2001;21(3):223-228.

  2. Tu W, Potena L, Stepick-Biek P, et al. T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease. Circulation. 2006;114(15):1608-1615.

  3. Westall G, Kotsimbos T, Brooks A. CMV-specific CD8 T-cell dynamics in the blood and the lung allograft reflect viral reactivation following lung transplantation. Am J Transplant. 2006;6(3):577-584.

  4. Bunde T, Kirchner A, Hoffmeister B, et al. Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med. 2005;201(7):1031-1036.

  5. Radha R, Jordan S, Puliyanda D, et al. Cellular immune responses to cytomegalovirus in renal transplant recipients. Am J Transplant. 2005;5(1):110-117.

  6. Lehto JT, Lemström K, Halme M, et al. A prospective study comparing cytomegalovirus antigenemia, DNAemia and RNAemia tests in guiding pre-emptive therapy in thoracic organ transplant recipients. Transpl Int. 2005;18(12):1318-1327.

  7. Humar A, Mazzulli T, Moussa G, et al. Clinical utility of cytomegalovirus (CMV) serology testing in high-risk CMV D+/R- transplant recipients. Am J Transplant. 2005;5(5):1065-1070.

  8. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998;338(24):1741-1751.

  9. Mañez R, Breinig MC, Linden P, et al. Posttransplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: the role of cytomegalovirus disease. J Infect Dis. 1997;176(6):1462-1467.

  10. Razonable RR, Burak KW, van Cruijsen H, et al. The pathogenesis of hepatitis C virus is influenced by cytomegalovirus. Clin Infect Dis. 2002;35(8):974-981.

  11. Tikkanen JM, Kallio EA, Bruggeman CA, Koskinen PK, Lemström KB. Prevention of cytomegalovirus infection-enhanced experimental obliterative bronchiolitis by antiviral prophylaxis or immunosuppression in rat tracheal allografts. Am J Respir Crit Care Med. 2001;164(4):672-679.

  12. Lemström KB, Koskinen PK, Bruning JH, Bruggeman CA, Lautenschlager IT, Häyry PJ. Effect of ganciclovir prophylaxis on cytomegalovirus-enhanced allograft arteriosclerosis. Transpl Int. 1994;7(Suppl 1):S383-S384.

  13. Radermacher J, Fricke L, Burg M, et al. Influence of prophylactic compared with early ganciclovir treatment on graft survival in renal allograft recipients [Abstract]. J Am Soc Nephrol 2006; 17:111A.

  14. Martelius T, Krogerus L, Höckerstedt K, Bruggeman C, Lautenschlager I. Cytomegalovirus infection is associated with increased inflammation and severe bile duct damage in rat liver allografts. Hepatology. 1998;27(4):996-1002.Kloover JS, Soots AP, Krogerus LA, et al. Rat cytomegalovirus infection in kidney allograft

  15.  recipients is associated with increased expression of intracellular adhesion molecule-1 vascular adhesion molecule-1, and their ligands leukocyte function antigen-1 and very late antigen-4 in the graft. Transplantation. 2000;69(12):2641-2647.

  16. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA. 1989;261(24):3561-3266.

  17. Westall GP, Michaelides A, Williams TJ, Snell GI, Kotsimbos TC. Bronchiolitis obliterans syndrome and early human cytomegalovirus DNAaemia dynamics after lung transplantation. Transplantation. 2003;75(12):2064-2068.

  18. Lowance D, Neumayer HH, Legendre CM, et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N Engl J Med. 1999;340(19):1462-1470.

  19. Ricart MJ, Malaise J, Moreno A, Crespo M, Fernández-Cruz L; Euro-SPK Study Group. Cytomegalovirus: occurrence, severity, and effect on graft survival in simultaneous pancreas-kidney transplantation. Nephrol Dial Transplant. 2005;20(Suppl 2):ii25-ii32, ii62.

  20. Potena L, Holweg CT, Chin C, et al. Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection. Transplantation. 2006;82(3):398-405.

  21. Hjelmesaeth J, Sagedal S, Hartmann A, et al. Asymptomatic cytomegalovirus infection is associated with increased risk of new-onset diabetes mellitus and impaired insulin release after renal transplantation. Diabetologia. 2004;47(9):1550-1556.

  22. Funch DP, Walker AM, Schneider G, Ziyadeh NJ, Pescovitz MD. Ganciclovir and acyclovir reduce the risk of post-transplant lymphoproliferative disorder in renal transplant recipients. Am J Transplant. 2005;5(12):2894-2900.

  23. Singh N, Wannstedt C, Keyes L, Wagener MM, Gayowski T, Cacciarelli TV. Indirect outcomes associated with cytomegalovirus (opportunistic infections, hepatitis C virus sequelae, and mortality) in liver-transplant recipients with the use of preemptive therapy for 13 years. Transplantation. 2005;79(10):1428-1234.

  24. Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG. Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med. 2005;143 (12):870-880.

  25. Hodson EM, Jones CA, Webster AC, et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet. 2005;365(9477):2105-2115.

  26. Humar A. Reactivation of viruses in solid organ transplant patients receiving cytomegalovirus prophylaxis. Transplantation. 2006;82(2 Suppl):S9-S14.

  27. Opelz G, Döhler B, Ruhenstroth A. Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report. Am J Transplant. 2004;4(6):928-936.

  28. Khoury JA, Storch GA, Bohl DL, et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant. 2006;6(9):2134-2143.

Volume : 5
Issue : 2
Pages : 727 - 730

PDF VIEW [105] KB.

From the 1Multiorgan Transplant Unit, CHU Rangueil, and the 2Laboratory of Virology, CHU Purpan, Toulouse, France
Address reprint requests to: Professor Lionel Rostaing, Multiorgan Transplant Unit, CHU Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059 Toulouse Cedex 9, France
Phone: +(33) 5 61 32 25 84
Fax: +(33) 5 61 32 28 64