r 2009 John Wiley & Sons A/S

Transplant Infectious Disease . ISSN 1398-2273

Review article

Cytomegalovirus infection and disease in the new era of immunosuppression following solid organ transplantation
                                       R.A. F|sher. Cytomegalovirus infection and disease in the new era of immunosuppression following solid organ transplantation. Transpl Infect Dis 2009: 11: 195^202. All rights reserved Abstract: As the most prevalent pathogen among transplant patients, cytomegalovirus (CMV) aects up to three-quarters of all solid organ transplant recipients.While we have made great strides in preventing CMV infection and disease in the early post-transplant period, late CMV infection and indirect eects due to viral immunomodulation remain problematic. Changing immunosuppression practices, including the increasing use of T-cell depleting induction antibodies, have the potential to aect the risk for CMV infection and disease, even in the face of good prophylactic and preemptive therapy.The purpose of this review article is to discuss the impact of CMV infection on longterm allograft outcomes and to re-evaluate the risks and management strategies for prevention of CMV in the framework of evolving modern immunosuppressive strategies.                                        R.A. Fisher
VCU Department of Surgery, Division of Transplantation Surgery, Virginia Commonwealth University, Richmond, Virginia, USA Key words: cytomegalovirus; solid organ transplantation; immunosuppression Correspondence to: Robert A. Fisher, MD, VCU Department of Surgery, Division of Transplantation Surgery, Virginia Commonwealth University, 1200 East Broad Street, West Hospital, 9th Floor South Wing, Richmond, VA 23298, USA Tel: 804 828 2461 Fax: 804 828 2462 E-mail: rasher@vcu.edu Received 26 September 2008, revised 13 November 2008, accepted for publication 16 November 2008 DOI: 10.1111/j.1399-3062.2009.00372.x Transpl Infect Dis 2009: 11: 195202

The long-term success of solid organ transplantation depends on a variety of factors. Despite a signicant decrease in rates of early acute rejection, long-term allograft and patient survival have not improved substantially despite the advent of modern immunosuppression. Several factors have been identied to explain this discordance, including the use of more marginal grafts, older donors, and immunologically sensitized recipients with co-morbid disease states (1). One modiable risk factor that has not been fully elucidated is the impact of virally mediated immunological events, specically cytomegalovirus (CMV) viremia and disease. CMV infection has traditionally been one of the most devastating infectious complications following solid organ transplantation. CMV seroprevalence in the general population approaches 60% in persons 20 years and older and increases with age (2). Therefore, the majority of donors and recipients will have had previous exposure to CMV. As a result, CMV infection will occur in 450% of solid or-

gan transplant recipients within the rst 3 months post transplant, if they do not receive antiviral prophylaxis (3). The direct eects of CMV viremia and disease are well known. Prevention of CMV infection can improve associated patient and allograft outcomes. The indirect eects of CMV, mediated by CMV-induced immunomodulation, have also been correlated with decreased patient and allograft survival (4). However, the crux of CMVs correlation with survival is just beginning to be understood in the midst of better detection methods and increased monitoring in the setting of more potent immunosuppression. Although we have improved our treatment and detection of CMV, persistent infection and viremia are likely contributing to co-morbid immunological events aecting our patients long term. The purpose of this review is to 1) discuss the impact of CMV infection on long-term allograft outcomes, 2) examine the indirect eects of CMV, and 3) describe special considerations that are needed in the modern era of immunosuppression.

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Current strategies to prevent CMV infection

In order to fully evaluate the direct and indirect eects of CMV in the setting of modern immunosuppression, it is important to review our current prevention strategies, universal prophylaxis, and preemptive therapy. Universal prophylaxis consists of administration of directed CMV antiviral therapy, such as valganciclovir, to all patients at risk for CMV infection for a period of time post transplant. This strategy is usually directed at the highest risk patients, focusing on patients who receive an allograft from a CMV positive donor yet lack adequate circulating CMV IgG to confer immunity against clinical re-infection (D 1 /R ). The normal duration of prophylaxis is 3^9 months post transplant.The second strategy is preemptive therapy.This strategy is mainly reserved for patients at moderate risk of CMV infection, specically recipients who have adequate amounts of circulating CMV IgG (R 1 ) regardless of donor serostatus. The advantage of this strategy is decreased universal drug costs and potential acquisition of booster immunity against CMV when reactivated following exposure to immunosuppression. In the preemptive strategy, treatment is initiated only after early indications of CMV antigenemia before the onset of clinical symptoms (5, 6). Universal prophylaxis is globally a more eective method to prevent CMV tissue invasive disease and associated mortality across all patients. Universal prophylaxis has also been associated with a reduction in non-CMVopportunistic infections when compared with preemptive therapy (6). A meta-analysis performed to assess the eects of universal prophylaxis on patient and graft survival did indicate an association with improved allograft survival. Specically, high risk (D 1 /R ) deceased-donor kidney transplant recipients who received CMV prophylaxis had signicant improvement in allograft survival at 3 years (79.4% with prophylaxis [ n 5 5426] versus 73.5% in those who did not receive prophylaxis [n 5 2908]; risk ratio [RR] 0.8, Po0.0001). Also, patients who received CMV prophylaxis were less likely to experience acute rejection within the rst year post transplant, 26.3% versus 32.4% in the non-prophylaxis group ( P 5 0.0001). These results were also consistent in heart, lung, and heart^lung recipients, with patients who received CMV prophylaxis having improved graft survival (7 ). When universal prophylaxis was compared with preemptive therapy, results were also similar. Kalil et al. (8) performed a meta-analysis on 17 trials in studies published between 1966 and May 2005 to compare universal prophylaxis with preemptive therapy in solid organ transplant recipients. Results indicated that both strategies were comparable in preventing CMV disease and reducing the inci-

dence allograft rejection. Khoury et al. (9) prospectively compared implementation of universal prophylaxis with preemptive therapy in 90 high-risk kidney transplant recipients over 1 year. In the preemptive group ( n 5 45) 2% of patients developed symptomatic CMV infection, while this infection occurred in 5% of patients receiving universal prophylaxis ( n 5 45) (P 5 0.362). Although the strategies appeared to equally prevent CMV disease, patients who received universal prophylaxis were less likely to experience bacterial and fungal infections and their associated mortality (8). Additional studies have evaluated the impact of CMV preventive therapies during the immediate post-transplant period. Both preemptive and universal prophylactic strategies have decreased the rate of symptomatic CMV infection to o10% (9, 10). However, these strategies fail to provide protection against long-term or persistent CMV viremia (11). V|remia following prophylaxis occurs at a rate of 4% in the lowest risk patients (D /R ) to 47% in the highest risk patients (D 1 /R ) (9, 12). The development of asymptomatic CMV infection and disease during the rst 100 days post transplant has been identied as an independent risk factor for mortality in patients at low or high risk for CMV infection (13). The atypical presentation and often persistent viremia that occurs with late infections has been implicated in several disease processes linked to the immunomodulatory eects of the CMV virus itself. The risk of CMV infection and disease is inuenced by post-transplant immunosuppression (Table 1) (14^19). However, studies that determine the true impact of immunosuppression on CMV viremia and disease are lacking. The majority of the published literature focuses on kidney recipients with multiple immunosuppressive regimens, which were not designed to evaluate the incidence of CMV. Published literature illustrates that there is a lack of uniform CMVdetection method and the evolution of the denition of CMV infection and disease. However, from these retrospective and post hoc analyses we can see that there is a correlation between the incidence of CMV infection and immunosuppression, regardless of the CMV disease prevention strategy chosen. Currently, according to the 2007 OPTN/SRTR Annual Report (1997^2006), 450% of kidney, 70% of pancreas, 10% of liver, 25% of heart, and 15% of lung transplant recipients receive lymphocyte-depleting induction therapy (20). In addition, mycophenolic acid, identied with increased risk of CMV infection and disease in pivotal studies, is being used in 470% of organ transplant recipients (21). W|th the use of more potent immunosuppressive regimens aimed at calcineurin or corticosteroid-sparing or to overcome immunological barriers to transplant, the true incidence and prevalence of ongoing viremia and its sequelae are unknown.

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Impact of delayed CMV infection

Use of early strategies to protect against CMV infection has been correlated with improved patient and allograft outcomes. However, evidence is still emerging to suggest that even though preemptive and universal prophylactic strategies delay the onset of CMV infection, even late infection can impact patient and allograft outcomes. Arthurs et al. (22) evaluated liver transplant recipients who were at the highest risk for CMV infection (D 1 /R ) to determine risk factors for CMV infection and its associated impact on patient and allograft outcomes. A total of 67 patients who were D 1 /R and received documented CMV prophylaxis for 3 months post transplant were included in this analysis. The majority of patients underwent liver transplantation secondary to hepatitis C cirrhosis (28%). Following CMV prophylaxis, 28% of patients developed CMV infection, 47% CMV syndrome, and 53% tissue invasive disease. Univariate analyses suggest that younger age, female gender, corticosteroid and mycophenolate mofetil use, and patients who experienced allograft rejection were more likely to experience CMV disease. However, these factors did not remain signicant in multivariate models. CMV disease and syndrome did not correlate with an increased risk of allograft loss or death, which the

authors attributed to a low risk of both these events in the cohort (22). Arthurs et al. (23) subsequently evaluated kidney transplant recipients who were at the highest risk for CMV infection (D 1 /R ) to determine risk factors associated with CMV infection and its impact on outcomes. A total of 176 patients who survived beyond 3 months post transplant were evaluated, including 13 patients who also received a pancreas ( n 5 4), liver ( n 5 8), or heart ( n 5 1). All patients received universal prophylaxis for 3 months post transplant and no patient experienced breakthrough CMV disease. Following the prophylactic period, 29% of patients developed CMV. The severity of infection was divided equally between CMV syndrome ( n 5 25) and tissue-invasive disease (n 5 26). Patients who experienced bacterial or fungal infections during the rst 3 months post transplant were more likely to experience CMV disease. However, no additional risk factors emerged. Patients who experienced late-onset CMV disease, but not CMV syndrome, were 2.5 times more likely to experience graft loss or death (23). The mounting body of evidence suggesting a signicant correlation between CMV infection and patient and allograft outcomes necessitates a careful evaluation of the immunomodulatory eects of CMV in the setting of modern immunosuppression.

Immunosuppression and cytomegalovirus (CMV) Infection Incidence Immunosuppression comparison Reference Basic-Jukic et al. (15) TheTricontinental Mycophenolate Mofetil Renal Transplantation Study Group (16) Kaufman et al. (17) Abou-Ayache et al. (18) Number of patients 499 497 Organ Kidney Kidney Group 1 CsA 1 CS 1 AZA or AZA 1 CS CMV disease 18% CsA 1 CS 1 AZA (n 5 162 ) CMV disease 6% Group 2 CsA 1 CS 1 MMF or MMF 1 CS CMV disease 20% MMF 2 g (n 5 171) CMV disease 11% Basiliximab 1 TAC 1 MMF CMV disease 5% Daclizumab 1 CsA 1 MMF 1 CS CMV infection/syndrome/ disease 39% ATG 1 CsA 1 AZA 1 CS CMV disease 0% MMF 3 g (n 5 164) CMV disease 7% P value Po0.01 P 5 NS

278 109

Kidney Kidney

Alemtuzumab 1 TAC 1 MMF CMV disease 4% Thymoglobulin 1 CsA 1 MMF 1 CS CMV infection/syndrome/ disease 51% Thymoglobulin 1 CsA 1 AZA 1 CS or Thymoglobulin 1 CsA 1 MMF 1 CS CMV disease 11%

P 5 NS P 5 NS

DeSanto et al. (19)

64

Heart

P 5 0.068

CsA, cyclosporine; CS, corticosteroids; AZA, azathioprine; MMF, mycophenolate mofetil; NS, not statistically signicant; TAC, tacrolimus; ATG, antithymocyte globulin.

Table1

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Immunomodulatory eects of CMV

CMV is a b-herpesvirus that infects its human host and then remains latent within the hosts myeloid cells for life (24). V|ral reactivation occurs during periods of inammation, cytokine release, and allogeneic stimulation. Often during the secondary CMV infection, the host immune response is slow, leading to prolonged viremia, which can be devastating in solid organ and hematopoietic transplant populations (25). Active replication of the virus, even in an immunocompetent host, can cause dysregulation of the adaptive immune response, making human CMV highly virulent (25). It has been demonstrated that the initial T-cell response directly correlates with the length and severity of CMV reactivation (24). Maintaining immunocompetent host defense against CMV depends on the activation and expansion of CD8 1 cytotoxicTcells (CTLs).V|ral peptides pp65 and pp150 stimulate production of interferon-gamma (IFN-g) and promote antigen-specic CTL proliferation, leading to eective control of viral replication (26). CTLs recognizing viral immediate early-1 (IE-1) gene products may also be important (27 ). Early adoptive transfer studies suggested that T-cell clones from CMV-seropositive donors (D 1 ) are capable of reconstituting anti-CMV CTL activity in immunocompromised patients undergoing allogeneic hematopoietic cell transplantation (28, 29). The eect was dependent on the expansion of CD4 1 helper T-cell function. Subsequent work in a small series of hematopoietic cell transplant recipients resistant to antiviral therapy revealed that transfusion of CMV-specic Tcells resulted in signicant reduction in viral load within a median time of 20 days following therapy (30). CD4 1 helper T cells also aect immunity to CMV. Indeed, anti-CMV immunity in immunocompetent hosts is believed to be associated with a hierarchy of cytokine production. Chronic CMV infection and low levels of viral antigen production have been associated with a tumor necrosis factor-alpha (TNF-a)4IFN-g4interleukin (IL)-2 hierarchy, while the production of IFN-g alone correlates with acute infection and high viral antigenic load (31^33). These ndings suggest that the pattern of helper T-cell cytokine production may drive eective antiviral CTL responses. The ability of the virus itself to elude host cell detection and defense is multifactorial. CMV has likely evolved over time with exposure to host defenses in the setting of more potent immunosuppression leading to signicant immunomodulation. Immunosuppressants that specically target T lymphocytes limit the transplant recipients

ability to clear the virus during primary infection or reactivation. Several mechanisms of immunomodulation have been proposed or observed in animal or in vitro models.The complex host^virus interaction is still not fully understood, but CMV-induced immunomodulation can be divided in 3 categories: 1) impaired cellular replication, 2) impaired cellular signaling, and 3) infected host cell resistance to host immune defense, also known as immune escape. Cells infected with CMV can become immortalized, through inhibition of internal Bcl-induced apoptosis (34). The characteristic leukopenia seen with active CMV infection is caused by viral suppression of the G1 and S phases of the cell cycle in many human cell lines (34). CMV can also impair intracellular and extracellular host cell signaling, specically through interference with glycosylation and protein folding, key functions in antigen recognition (35). CMV interrupts the development of the T-cell receptor, major histocompatibility complexes (MHCs), and other signaling proteins (34, 35). CMV also encodes for membrane-bound proteins that interrupt normal lymphocyte tracking during an immune response. These membrane-bound proteins induce cytokine release, which induces chemotaxis of neutrophils to areas of infection, increasing the pathogenic virulence of the virus. This increases inammation, which can exacerbate viral dissemination (34). CMV is further able to escape the host immune system through reduction in the expression of both MHC Class I and MHC Class II proteins (25, 34). This phenomenon leads to a reduction in CD8 1 lymphocyte surveillance, which is the primary cell responsible for recognition of CMV-infected cells (25, 36). La Rosa et al. (37 ) recently demonstrated that in high-risk (D 1 /R ) liver transplant recipients who develop CMVdisease following valganciclovir prophylaxis there is higher expression of programmed death (PD-1) in CMV-specic and nonspecic CD8 1 cells when compared with healthy controls. CD4 1 T helper cells specic for CMValso appear to be a necessary component of the immunologic response to prevent CMV infection (36). These T-helper cells secrete IFN-g, TNF- a, and several other cytokines in the absence of IL-2 (36). A reduction in natural killer cell activity has also been associated with increased severity of CMV infection, in the setting of decreased expression of MHC Class I on virally infected cells (36).The inability of the host immune system to recognize and attack infected cells extends the persistence of viremia and may lead to additional manifestations of CMV beyond those specic to the cells it infects. As a result, the true implications of CMV viremia and additional eects on the immune system continue to be elucidated.

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Indirect eects of CMV viremia

Risk factors for CMV indirect eects include CMV seropositivity, asymptomatic low-level CMV viremia, elevated viral load, and CMV disease. Asymptomatic viremia and reactivation of latent CMV are considered major factors contributing to indirect eects (38). Opportunistic infections The increased incidence of concurrent opportunistic viral, fungal, and bacterial infections in the setting of CMV infection has been well characterized in the literature. The immunomodulatory properties of CMV are attributed to solid organ transplant recipients increased vulnerability to these infections. For example, the hepatitis C virusinfected liver transplant recipients who have reactivation of CMV experience signicantly higher rates of allograft failure and mortality. Evidence suggests that viral suppression, through administration of prophylactic therapy, provides a proportionate decline in these opportunistic infections (39). Accelerated allograft rejection and loss CMV tissue-invasive disease manifested as hepatitis has also been described as a leading cause of allograft destruction in liver transplant recipients. Adult liver allograft recipients transplanted between 1991 and 2000 ( N 5 229) were retrospectively analyzed to determine if a correlation existed between CMV infection within the allograft and graft outcomes (40). CMV tissue-invasive disease, specically in the liver, was observed in 11% (26/229) of the recipients. Although all CMV infections were successfully treated, approximately 4% (1/26) developed hepatic thrombosis, bacterial infections, and eventually died from liver abscesses and fungal infections. Patient and graft survival at 4 years were 81% and 75%, respectively. More recently, the immunomodulatory eects of CMV infection have been linked to accelerated chronic allograft rejection. Fateh-Moghadam et al. (41) evaluated 103 heart transplant recipients to determine if patients who were CMV immune globulin (Ig)G/IgM positive, indicating active infection, had a higher incidence of transplant vasculopathy. The investigators were able to demonstrate that patients who were CMV IgG/IgM positive were more likely to have more advanced, calcied coronary lesions when compared with other patients. These results are also evident in lung transplant recipients. Chmiel et al. (42) prospectively evaluated 96 lung transplant recipients to determine the impact of CMV prophylaxis and disease on

development of bronchiolitis obliterans, patient and allograft survival compared with historical controls. CMV prophylaxis reduced the incidence of CMV infection by 48%; however CMV infection still occurred in 11 patients following the prophylactic period. Patients who received CMV prophylaxis were less likely to develop bronchiolitis obliterans compared with historical controls (43% versus 60%, P 5 0.002). Also, patients receiving prophylaxis were less likely to experience graft loss secondary to bronchiolitis obliterans or die, when compared with historical controls at 5 years (18% versus 50%, P 5 0.018). Diabetes and cardiovascular disease CMV infection has also been implicated as a risk factor for new-onset diabetes mellitus in renal transplant recipients. Leung et al. (43) describe 2 patients who developed new-onset diabetes with the onset of late CMV infection. Both patients were non-obese and on low doses of corticosteroids. Blood sugars normalized in both patients once the CMV was treated and viral loads became undetectable. The authors postulated that the development of diabetes in the setting of CMV infection is related to direct b-cell toxicity or interruption of normal metabolic pathways within the liver during infection. The association between early CMV and long-term mortality was investigated retrospectively in kidney transplant recipients over a 5 -year period (1994^1997 ) (13). Patients categorized as high risk for mortality (n 5 99), or as low risk for mortality ( n 5 372) were monitored for asymptomatic CMVantigenemia, and followed for the next 66.6 months. The incidence of overall and cardiovascular mortality was 14% low risk versus 31% high risk, and 3.5% low risk and 16% high risk, respectively. Asymptomatic CMV infection ( n 5 186; RR 2.75; 1.53^4.94, P 5 0.001) and CMV disease (n 5 110; RR 2.58; 1.35^4.94, P 5 0.004) were signicant risk factors and implicated in an increase of overall long-term mortality that was independent of the mortality risk. Although the indirect eects of CMV are not fully understood, the transplant community must seek alternative methods to prevent the long-term sequelae of CMV infection.

Special considerations in modern era of transplant immunosuppression

Our understanding of the immunomodulatory eects of CMV in the clinical context of chronic immunosuppression strongly suggests that overimmunosuppression should be

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avoided in solid organ transplant recipients. While no one immunosuppressant has been consistently associated with increased risk of developing CMV infection or disease, several lines of evidence suggest that sirolimus may be protective. In one recent study, the hazard ratio for CMV reactivation was 0.46 (95% condence interval [CI] 0.27^ 0.78; P 5 0.004) in hematopoietic cell transplant recipients treated with sirolimus and tacrolimus for graft-versus-host disease prophylaxis (44). In renal transplant recipients, the results of one retrospective case-control study and 2 randomized studies have revealed a lower incidence of CMV infection among patients treated with sirolimus (45^47 ). In the randomized study conducted by Buchler et al. (46), the incidence of CMV infection was 6% in patients treated with sirolimus, compared with 23% in patients who received cyclosporine ( Po0.01). Similarly, Kreis et al. (47 ) reported an incidence of CMV viremia of 5% and 21% (Po0.05) among patients treated with sirolimus or cyclosporine, respectively. While other isolated studies have failed to corroborate these ndings, the balance of evidence suggests that sirolimus may exert a protective eect against CMV infection, possibly through the inhibition of viral protein synthesis (48). Nevertheless, today, our transplant recipients are at the highest risk for CMV-associated sequelae secondary to the signicant proportion of solid organ transplant recipients who now receive T lymphocyte-depleting induction. Several centers are also attempting to cross previously contraindicated immunologic barriers to allow transplantation of highly sensitized individuals by using large amounts of immunosuppression. In the absence of a robust T cell immune response, the infected host will be at signicant risk for viral activation or reactivation. This increased net state of immunosuppression should cause clinicians to reevaluate their denition for high-risk transplantation to incorporate CMV serostatus as a signicant variable that can contribute to long-term outcomes. Anti-viral therapy is expensive, may induce resistance, and has signicant hematological toxicity, making its value in the prevention of the indirect eects limited. Therefore, the potential role for passive immunity in high immunologic risk or patients who receive a high net level of immunosuppression post transplant may be considered a viable option to prevent CMV infection and improve patient and allograft outcomes. A meta-analysis was conducted to evaluate the prophylactic impact of CMV-immune globulin, intravenous (IGIV) administration on CMV infection, disease, and mid-term survival in kidney transplant recipients (49, 50). Results from 11 trials indicated that CMV-IGIV is eective against CMV disease and associated death. Patients treated with CMV-IGIVprophylaxis had a lower incidence of clinical disease, and no association with hematologic complications. The reduction in overall mortality was attributed to re-

duced CMV-associated disease, and a lower incidence in opportunistic infections (49). The authors concluded that CMV-IGIVcould provide a valuable therapeutic tool for the prevention of CMV disease, and improvement of both overall and CMV-related mortality. A recent study by Potena et al. (51) describes the eect of clinical and subclinical viral replication through antiviral prophylaxis on outcomes in heart transplant recipients. V|ral replication in patients at risk for CMV (D 1 /R , D 1 /R 1 , D /R 1 ) receiving CMV prophylaxis were compared with patients not at risk (D /R ). The investigators were able to demonstrate that viral replication did not occur in patients not at risk for CMV infection, while all patients at risk did experience CMV replication. CMV replication in at-risk patients correlated with D/R serostatus. For example, seronegative recipients (R ) who received an organ from a seropositive donor (D 1 ) displayed viral replication activity within their white blood cells earlier than other patients. Anti-viral therapy decreased the magnitude of viral replication, but could not completely impede viral growth. V|ral replication within host lymphocytes was predictive of systemic CMV DNA detection. The amplitude of viral replication following CMV prophylaxis termination also correlated with recipient serostatus (51). F|ndings from this study suggest that, despite prophylaxis, subclinical viral replication occurs in the setting of posttransplant immunosuppression. Therefore, the eects of the CMV virus may be present earlier in a patients clinical course than previously thought, allowing CMV to exert its immunomodulatory eects. The ecacy of preemptive CMV-IGIV therapy and the incidence of opportunistic infections including CMV was also evaluated in cardiac transplant patients with severe or moderate hypogammaglobulinemia (HGG) (50). Intense immunosuppressive therapy following heart transplantation is associated with severe HGG and a consequential increase in risk for rejection and opportunistic infections. Patients with severe HGG administered preemptive CMVIGIV replacement therapy had fewer episodes of rejection and opportunistic infections when compared with the control group. The incidence of CMVdisease in moderate HGG patients also decreased with preemptive CMV-IGIV treatment (50).

Conclusions
The direct eects of CMV infection and disease are well known, while the impact of the indirect eects of CMV infection is now being realized. The impact of CMV viremia and infection under modern immunosuppression warrants

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further investigation in solid organ transplantation. Additional anti-viral therapy or monitoring beyond the rst 100 days post transplant may be necessary to impact long-term patient and allograft outcomes. Based on evidence of indirect eects of CMV on long-term outcomes, perhaps we should consider this a new era of CMV infection and evaluate strategies to improve long-term patient and graft survival.

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15.

16.

Acknowledgements: The author acknowledges the research and development assistance of Dr Carolynn Pietrangeli and Dr G. Mark Baillie, CTI Clinical Trial and Consulting Services, to produce the manuscript.
17.

18.

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