The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients

Transplantation Reviews xxx (2014) xxx–xxx

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Transplantation Reviews

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The impact of the prevention strategies on the indirect effects of CMV infection insolid organ transplant recipients

Antonio Roman a,⁎, Nicolás Manito b, Josep Maria Campistol c, Valentín Cuervas-Mons d, Luis Almenar e,Manuel Arias f, Fernando Casafont f, Domingo del Castillo g, María G. Crespo-Leiro h, Juan F. Delgado i,J. Ignacio Herrero j, Paloma Jara k, José M. Morales i, Mercedes Navarro k, Federico Oppenheimer c,Martín Prieto e, Luis A. Pulpón d, Antoni Rimola c, Daniel Serón a, Piedad Ussetti d

ATOS working group 1

a Hospital Vall d'Hebrón, Barcelona, Spainb Hospital de Bellvitge, Barcelona, Spainc Hospital Clínic, Barcelona, Spaind Hospital Puerta de Hierro, Madrid, Spaine Hospital La Fe, Valencia, Spainf Hospital Marqués de Valdecilla, Santander, Spaing Hospital Reina Sofía, Córdoba, Spainh Complejo Universitario A Coruña, La Coruña, Spaini Hospital 12 de Octubre, Madrid, Spainj Clínica Universitaria de Navarra, Pamplona, Spaink Hospital La Paz, Madrid, Spain

a b s t r a c t

Transplant recipients receiving immunosuppressive therapy are at increased risk of active cytomegalovirus(CMV) infection and disease. Without appropriate prophylaxis, as many as 80% of solid organ transplantrecipients may experience CMV infection. In addition to the direct effects of CMV, infection may be associatedwith a range of indirect effects, including an increase in risk of other infections, as well as a higher incidence ofrejection, graft loss and death. The indirect effects of CMV infection can vary depending on the transplantedorgan. For example, CMV-infected kidney transplant recipients may be at increased risk of cardiovasculardisease and diabetes, while CMV infection in liver transplant recipients may potentiate hepatitis C infectionand increase the risk of post-transplant lymphoproliferative disease. Indirect effects result from a number ofpathological processes, including immune modulation and immunosuppression, generation of cytotoxic, pro-inflammatory responses, and smooth muscle proliferation. Prophylactic treatment with antiviral medicationcan reduce the risk of CMV disease, thereby improving graft survival and overall outcomes, particularly inkidney and heart transplant recipients. Antiviral prophylaxis should be considered for all patients at risk ofCMV infection after solid organ transplantation. In this paper we review the main indirect effects of CMVinfection in solid organ transplant recipients, and the impact of CMV prophylaxis on these effects.

© 2014 Elsevier Inc. All rights reserved.

1. Introduction

Cytomegalovirus (CMV) infection is an important complication inpatients receiving solid organ transplants (SOT). The virus is wide-spread, some studies estimating that as many as 97% of the populationmay be infected, the virus establishing life-long latency after primaryinfection [1]. As a result, transplant recipients receiving immunosup-

⁎ Corresponding author at: Department of Pulmonology, Hospital Vall d’Hebron, Passeigde la Vall d'Hebron, 119-129, 08035 Barcelona, Spain. Tel.: +34 934 89 30 00.

E-mail address: [email protected] (A. Roman).1 Aula sobre Trasplantes de Órganos Sólidos (ATOS)— the Solid Organ Transplantation

Classroom working group.

0955-470X/$ – see front matter © 2014 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.trre.2014.01.001

Please cite this article as: Roman A, et al, The impact of the preventiotransplant recipients, Transplant Rev (2014), http://dx.doi.org/10.1016/

pressive therapy are at increased risk of active CMV infection anddisease,with 30%–80% of SOT recipients experiencing CMV infection inthe absence of appropriate prophylactic treatment [2].

The risk of CMV disease in transplant recipients varies accordingto the organ transplanted, with the lowest rates of CMV infection anddisease seen in kidney recipients (8%–32% and 8%, respectively) [3].Heart transplant recipients are at similar risk of CMV infection tokidney recipients (9%–35%), but are at much higher risk of developingCMV disease (29%). The risk of CMV infection and disease in livertransplant recipients are 22%–29% and 29%, respectively, while reci-pients of lung or heart–lung transplants appear to be at the highestrisk both of CMV infection and disease (both ~ 40%) [3]. The risk isalso affected by the CMV serostatus of the donor and recipient, with

n strategies on the indirect effects of CMV infection in solid organj.trre.2014.01.001

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2 A. Roman et al. / Transplantation Reviews xxx (2014) xxx–xxx

transplantation of a seropositive organ to a seronegative recipient(D+/R−) placing the recipient at the highest risk of CMV disease[2]. In a recent publication, monitoring CMV-specific cell-mediatedimmunity by Quantiferon- assay, which measures the interferon-γresponses to a range of T-cell epitopes of CMV proteins, showedevidence to appropriately stratified D+/R− patients at low, inter-mediate, or high risk of developing subsequent CMV disease afterprophylaxis [4]. Conversely, transplantation of a seronegative organto a seronegative donor (D−/R−) carries a very low risk of infec-tion. The degree of immunosuppression also plays a role, with highlypotent immunosuppressants, particularly anti-lymphocyte anti-bodies, substantially increasing the risk of CMV [2,3].

Before transplantation takes place, both donor and recipient areassessed for CMV status, using specific and sensitive serologicalmethods based on the detection of IgG antibodies [2]. Recipients whoare CMV seronegative should receive repeated assessments in theperiod leading up to transplant surgery. After transplantation, viro-logical assessment is carried out to detect asymptomatic viral repli-cation, and patients are monitored for signs and symptoms of CMVdisease. Virus detection relies on cultures, antigen detection andmolecular methods. In addition, quantitative techniques may be ofvalue, as replication intensity is related to disease development andrelapse risk [2]. Viral syndrome can be detected based on levels ofviral pp65 antigen in peripheral blood leukocytes, with moleculartests providing the main alternative [5,6]. If monitoring is carried outwith a view to pre-emptive treatment, molecular techniques may bepreferable [2]. Immunological monitoring of CMV-specific T cells mayalso assist in the identification of patients at high risk of viralreplication. Where focal CMV disease (e.g. of the gastrointestinal tractor retina) is suspected, diagnosis is carried out on the basis of tissuesamples where possible, as blood CMV antigen levels may be low [2].

CMV disease typically takes the form of viral syndrome, with flu-like symptoms (fever, malaise), with or without myelosuppression(leukopenia, thrombocytopenia) [1,3,7]. CMV infection may also leadto invasive disease in a range of tissues, including pneumonitis, hepa-titis, retinitis and gastrointestinal disease, with the grafted organbeing particularly susceptible [1,7]. In addition, CMV infection isassociated with a wide range of indirect effects that depend on thetransplanted organ (Table 1).

In this paper we review the main indirect effects of CMV infectionin SOT recipients, and the impact of CMV prophylaxis on these effects.

2. Indirect effects of CMV

2.1. General indirect effects of CMV infection

CMV infection results in immunosuppression, and thus post-transplant CMV infection has been linked with an increased risk ofsome bacterial infections (including pneumonia and nocardiosis) andinvasive fungal diseases such as aspergillosis [2,3,8]. CMV infectionmayalso be associated with reactivation of latent β herpes viruses, such ashuman herpesvirus (HHV) 6 and HHV-7, which have been linked withan increased risk of allograft rejection [3]. Replication of CMV has alsobeen associated with immunosenescence as a result of increased

Table 1Indirect effects associated with CMV infection and/or disease in solid organ transplant recip

General effects Kidney Liver

• Bacterial infections• Fungal infections• Herpesvirus reactivation• Immunosenescence

• Acute rejection• Graft loss• Death• Cardiovascular events• Chronic allograft nephropathy• Diabetes

• Chronic rejection• Graft loss• Interaction with H• Post-transplant HC• PTLD• Diabetes

HCV = hepatitis C virus; PTLD = post-transplant lymphoproliferative disease.


proliferation of CD27- and CD28-negative CMV-specific CD8+ T cells[9]. The clinical implications of this finding are, however, unclear.

2.2. Specific indirect effects of CMV infection

2.2.1. Kidney transplantationIn kidney transplant recipients (including combined kidney–

pancreas recipients), numerous studies have shown that CMVinfection is associated with an increased risk of acute allograft rejec-tion [10–16]. CMV may also play a role in chronic graft dysfunction,with many studies suggesting a relationship between chronic allo-graft nephropathy (CAN) or chronic rejection and CMV disease orinfection (particularly for high viral loads) [10,17–22]. Others how-ever, have found no definitive link between CMV infection andchronic rejection [23]. Similarly, while some studies have shown alink between CMV infection and allograft loss [10,20,24–27] ormortality [27–29], studies in which graft loss is corrected for deathshow that CMV infection is no longer associated with graft loss[18,28,30], although progression to CMV disease remains a significantrisk factor for graft loss in some studies [18,30].

CMV infection in renal transplant recipients also appears to beassociated with an increased incidence of cardiovascular disease,including arrhythmias, congestive heart failure, atherosclerosis andvessel occlusion [31–33]. Multivariate analysis of prospective datafrom 121 consecutive patients, however, found that pre-existingevents were the only significant predictor of cardiovascular eventswithin 1 year after transplantation [32]. There have also been reportsof a link between CMV infection and diabetes in renal transplantrecipients [34,35], although other studies have found no evidence ofan increased risk of diabetes [36].

2.2.2. Liver transplantationIn liver transplantation, CMV appears to be associated with an

increased risk of chronic rejection, graft loss and mortality [37–43].Late CMV infection, however, does not show the same relationshipwith chronic rejection [44], and no relationship between CMV andvanishing bile duct syndrome – a specific form of chronic rejection –

has been established [45].CMV reactivation in liver transplant recipients has been shown

to interact with other important viruses. In hepatitis C virus (HCV)-infected recipients, for example, co-infection with CMV is associatedwith more severe fibrosis [39,46], as well as a tendency towardsgreater hepatitis activity index and HCV viral load [39]. HCV and CMVhave both been identified as risk factors for diabetes in liver trans-plant recipients [47]. Co-infection with CMV and Epstein–Barr virusis associated with an increase in the risk of post-transplant lym-phoproliferative disease (PTLD) [48].

2.2.3. Heart transplantationAllograft vasculopathy is an important complication of heart

transplantation, and a significant link between CMV infection and theincidence and severity of vasculopathy has been established in pros-pective and retrospective studies [49–54]. In addition, these studieshave shown that CMV infection is also associated with increased risk

ients [2].

Heart Lung

CVV recurrence

• Allograft vasculopathy• Graft loss• Death• Systemic endothelial dysfunction• Acute cellular rejection• Renal dysfunction

• Bronchiolitis obliterans• Graft loss• Death



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3A. Roman et al. / Transplantation Reviews xxx (2014) xxx–xxx

of graft loss and/or death [49,50,52,55]. Furthermore, there isevidence that CMV infection in heart transplant recipients may beassociated with chronic endothelial dysfunction in the systemiccirculation [56,57] and significantly increased risk of renal dysfunc-tion [58].

2.2.4. Lung transplantationThe most frequently described indirect effect of CMV in lung

transplant recipients is chronic rejection in the form of bronchiolitisobliterans (BO) [2,59], an obstructive condition involving inflamma-tion and fibrosis in the walls of the bronchioles [60]. While a sig-nificant association between CMV and BO has been observed [61–66],it should be noted that no definitive causal relationship has beenestablished [2]. CMV in lung transplant recipients has also beenassociated with increased mortality and graft loss [66–68].

2.3. Pathophysiology of indirect effects

CMV infects a wide range of cells, including endothelial andepithelial cells in several organs, smooth muscle cells, fibroblasts,neurons, and immune cells such as monocytes, macrophages anddendritic cells [69,70]. One of the major mechanisms by which CMVcauses indirect effects is through modulation of the immune system.CMV replication leads to activation of protein synthesis and pro-duction of Fc receptors, adhesion molecules and pro-inflammatorycytokines [3,7,71–73]. This in turn leads to increased display ofmajor histocompatability complex (MHC) II antigens in the allograft,which, together with the pro-inflammatory environment, leads toendothelial cell damagemediated by alloreactive T cells [3]. Migrationand proliferation of smooth muscle cells in the lesion also play arole in the accelerated vasculopathy seen in transplant recipients [73].Allograft damage may also be the result of modulation of the nitricoxide synthase pathway, leading to creation of intracellular reactiveoxygen species in vascular smooth muscle cells, and coagulationresulting from activity of factor von Willebrand, factor VIII andfibrinogen [71].

In addition to specific allograft effects, the modulatory effects ofCMV lead to a generalized immunosuppression. This is caused by theevolved mechanisms of CMV to evade the host immune system,including both the innate and adaptive arms [72,74]. The mechanismsinclude blockade of the processing and display of CMV-specific earlyantigens and impaired cytotoxic T cell responses, andmay explain theincreased risk of opportunistic infections in CMV-infected transplantrecipients [7,72,74]. Some authors have speculated that virus-inducedactivation of antigen-presenting cells, particularly plasmacytoiddendritic cells, may contribute to T cell-independent activation ofB-cells and to the generation of autoimmune process [75]. Nonspecifichyper activation of humoral immunity may also impede the deve-lopment of specific B-cell responses and although may not affectviral efficiency, but it could have important clinical implications forCMV infected patients, such as in the development of graft rejectionin SOT recipients.

The mechanisms by which CMV induces other indirect effectsare less well characterized than those involved in allograft damageand infection. For example, post-transplant diabetes is presumablythe result of direct infection of pancreatic β-cells and induction of acytotoxic inflammatory response. While reduced insulin secretionhas been observed in CMV-infected transplant recipients [34,35],no definitive causal relationship between CMV and diabetes hasbeen established.

One area where there are conflicting data is in the role of CMV incancer risk in transplant recipients. In non-transplant patients,various studies have shown the presence of CMV DNA, proteins andvirus particles in tumor cells from a range of organs [74]. Furthermore,in vitro experiments suggest that CMV infection may interfere withcellular signaling pathways, leading to increased cell survival and


angiogenesis, together with alterations in cell motility and adhesion.In transplant recipients, however, there is evidence that CMV infec-tion increases the number of tumor-reactive γ δ T cells [76]. This isconsistent with studies showing no increase in malignancy, or even adecreased risk, in CMV-infected transplant recipients [36,76]. Fur-thermore, a study of CMV prophylaxis vs. pre-emptive treatmentfound that half of deaths in the prophylaxis arm were the result ofmalignancy [77].

3. Impact of CMV prophylactic strategies on indirect effects

In CMV prophylaxis, antiviral medication (acyclovir, valaciclovir,ganciclovir or valganciclovir) is given to at-risk patients, regardless ofclinical suspicion and microbiological evidence of infection. Overall,studies have shown a 58%–80% reduction in the incidence of CMVdisease with prophylaxis compared with placebo or no prophylaxis[2]. Data on indirect effects are, however, less clear, with conflictingresults from a series of meta-analyses looking across the range of solidorgan transplantation. A meta-analysis of 17 trials (n = 1980) foundthat recipients of SOT who receive CMV prophylaxis had asignificantly lower incidence of acute rejection (odds ratio [OR],0.74; 95% confidence interval [CI]: 0.59–0.94), opportunistic in-fections (0.49; 0.36–0.67) and death (0.62; 0.40–0.96) comparedwith those who receive placebo or no therapy [78]. A secondsystematic review (19 trials; n = 1981) published in the same year,however, found that, while prophylaxis reduced all-cause mortality(relative risk [RR], 0.63; 95% CI: 0.43–0.92), CMV-related mortality(0.26; 0.08–0.78), and bacterial (0.65; 0.44–0.96) and protozoal (0.31;0.01–0.99) infections compared with placebo or no prophylaxis, therewas no benefit in terms of acute rejection (0.90; 0.78–1.05), fungalinfection (0.58; 0.19–1.73) or graft loss (0.74; 0.47–1.17) [79]. Theauthors later carried out a more extensive meta-analysis (34 trials;n = 3850) on behalf of the Cochrane Collaboration, with similarresults [80].

One of the largest studies of CMV prophylaxis was carried outusing data from the Collaborative Transplant Study (CTS), whichinvolved N35,000 patients [81]. Main results from this study regardinggraft survival and rejection episodes are collated in Table 2. Here wereview data from the CTS, together with some other key trials of CMVprophylaxis.

3.1. Kidney transplantation

In the CTS, CMV prophylaxis was significantly associated withimproved graft survival after 3 years in D+/R− patients (RR, 0.80;95% CI: 0.73–0.89; p b 0.0001) [81]. In these patients, CMV prophy-laxis was also associated with a lower overall mortality (RR, 0.71; 95%CI: 0.61–0.83; p b 0.0001). In D+/R+ patients there were smallimprovements in 3-year graft and patient survival, but these werenot statistically significant.

The efficacy of prophylactic treatment with ganciclovir wasevaluated in an open-label comparative study in which 148 renaltransplant recipients were randomized 1:1 to receive prophylaxis orpre-emptive therapy [82]. All patients were adults at risk of CMVdisease (donor, recipient or both seropositive for CMV, but currentlynegative for CMV viral load). Prophylaxis consisted of 1000 mg oralganciclovir three times daily (t.i.d.) starting within 48 h after trans-plantation and continued until day 90. Patients in either arm whotested positive for CMV DNA (≥400 copies/mL) during the studyreceived 5 mg/kg bodyweight intravenous ganciclovir twice daily(b.i.d.) for at least 10 days until CMV DNA was b 100 copies/mL ontwo consecutive assessments, followed by secondary prophylaxiswith 1000 mg oral ganciclovir t.i.d. for at least 14 days. After 12months, there were no differences between the prophylaxis and pre-emptive arms in biopsy-proven acute rejection (BPAR) (n = 14 vs.n = 18, respectively) or renal function (mean creatinine clearance:



Table 2Results of the Collaborative Transplant Study in solid organ transplant recipients receiving CMV prophylaxis in comparison with those not treated.

Type 3-year graft survival, % Rate of rejection treatment after 1 year, %

CMV prophylaxis No CMV prophylaxis RR P-value CMV prophylaxis No CMV prophylaxis P-value

Kidney 79.4 73.5 0.80 b0.0001 26.3 32.4 0.0001Liver 68.1 73.4 1.18 NS 17.5 27.1 NSHeart 78.7 71.1 0.71 0.0001 46.1 55.6 0.0037Lung 58.7 44.7 0.53 b0.0001 42.1 64.3 NS

IC: Interval of confidence; NS: not significant; RR: relative risk.Data are shown for first organ transplants in CMV-negative recipients of kidneys from CMV-positive donors.Opelz G, Dohler B, Ruhenstroth A. Cytomegalovirus prophylaxis and graft outcome in solid organ transplantation: a collaborative transplant study report. Am J Transplant2004;4:928–36.


54.0 ± 24.9 vs. 53.1 ± 23.7 mL/min). Overall survival was alsosimilar in the two arms. After 4 years of follow-up, however, patientsin the prophylaxis arm had a significantly lower incidence of graftloss (7.8%) compared with the pre-emptive arm (21.7%; p = 0.0425).When censored for death, a substantial difference remained, althoughit was no longer statistically significant (4.8% vs. 16.1%; p = 0.0621).Both treatments were well tolerated, with a higher incidence ofleukopenia in the prophylaxis arm (14.9% vs. 1.3%; p = 0.0045), and ahigher incidence of CMV-related adverse events with pre-emptivetreatment (33 vs. 15 events).

To determine the impact of duration of prophylactic treatment, adouble-blind study was conducted in 326 adult single-organ renaltransplant recipients at high risk of CMV (D+/R− transplantation)[83]. Patients were randomized to receive valganciclovir 900 mg/dayfor 200 days, or for 100 days followed by 100 days of placebo, withtreatment initiated within 10 days after transplantation. Overall,there was a numerically lower incidence of BPAR in the 200-daygroup (11%) vs. the 100-day group (17%; p = 0.114). The rate of graftloss was very low (2% in each arm). Renal function was also similarin the two arms, and there was no difference in the incidence ofnew-onset diabetes (12% vs. 11% in the 200- and 100-day arms,respectively). The longer duration of prophylaxis was, however, asso-ciated with a significantly lower incidence of opportunistic infections(13%) compared with 100 days (27%; p = 0.001). Safety and tole-rability were similar within the two regimens, althoughmore patientsin the 200-day arm (4%) discontinued the study as a result of leuko-penia compared with the 100-day arm (b1%).

The feasibility of pre-emptive high-dose ganciclovir/valganciclovirto overcome ganciclovir resistance was recently evaluated in fiverenal transplant recipients, including one kidney-pancreas recipient,and one liver transplant recipient [84]. Four of the patients receiveduniversal prophylaxis with valganciclovir, while the remaining tworeceived pre-emptive valganciclovir treatment for individual replica-tion episodes. All were switched to high-dose intravenous ganciclovir(7.5–10 mg/kg/12 h) or oral valganciclovir (1350–1800 mg/12 h),corrected for creatinine clearance, after detection of ganciclovir resis-tance mutations, and all six responded to treatment. Four patientsexperienced neutropenia, but only one required treatment. Theauthors therefore suggest that high-dose ganciclovir/valgancicloviris a viable option for the treatment of resistant CMV replication.

3.2. Liver transplantation

In liver transplant recipients included in the CTS, no significantimprovement in graft survival was observed in D+/R− patients re-ceiving CMV prophylaxis [81]. While there was a numerical reductionin the rate of treated rejection in the first year (17.5%with prophylaxisvs. 27.1% without), the difference was not statistically significant.

A randomized comparative study of prophylaxis with oral acy-clovir vs. oral ganciclovir enrolled 110 patients undergoing orthotopicliver transplantation who were seropositive for CMV before surgeryand showed no signs or symptoms of CMV disease [85]. All patients


initially received intravenous ganciclovir (6 mg/kg/day) for 14 days,starting the day after surgery. They then received ganciclovir(1000 mg every 8 h) or acyclovir (800 mg every 6 h) until day 100.At 1 year, survival was similar in the ganciclovir (89/110; 81%) andacyclovir (93/109; 85%) arms. Both treatments were well tolerated,with no clinical adverse events attributed to either study drug. Fiveganciclovir-treated patients (5%) and one acyclovir-treated patient(1%), however, developed severe leukopenia, and 16 ganciclovir-treated patients (15%) discontinued study medication as a result ofleukopenia (p b 0.001 vs. acyclovir).

In a retrospective chart review, data were analyzed from 66 high-risk patients (D+/R−) who received one of three prophylactic regi-mens: valganciclovir (900 mg/day; n = 27), oral ganciclovir(1000 mg every 8 h; n = 17), or intravenous ganciclovir (6 mg/kg/day; n = 22) [86]. In total, seven episodes of rejection were reported,all of which occurred after CMV infection, and four of which occurredin patients with CMV disease. The incidence of infections was similarbetween the three prophylactic regimens.

CMV infection has been associated with increased severity of HCVrecurrence suggesting that targeted prophylaxis against CMV mightreduce the impact of its indirect effects on posttransplant outcomesin HCV-infected liver transplant recipients. However, no potentialbenefits have been found up to date [87].

3.3. Heart transplantation

Data from the CTS showed that the administration of CMV pro-phylaxis to D+/R− heart transplant recipients was significantlyassociatedwith improved graft survival after 3 years (RR, 0.71; 95% CI:0.60–0.84; p = 0.0001) [81]. In addition, prophylaxis significantlyreduced the incidence of treated rejection in the first year (46.1% vs.55.6%; p = 0.0037). In D+/R+ recipients, the benefit on graft losswas smaller, but still statistically significant (RR, 0.85; 95% CI: 0.73–0.98; p = 0.0240).

In an observational, prospective, large-scale, multicenter study in asample of 199 heart transplanted recipients receiving currentimmunosuppressive protocols, prophylactic treatment was asso-ciated with a lower, but not significant, frequency of positive CMVviremia (41% vs. 71%; P = 0.079) and significantly delayed mediantime to a positive test (88 vs. 35 days; P = 0.014) [88]. The mostcommonly used prophylactic treatment was IV ganciclovir (45%),followed by oral valganciclovir (30%), or a combination of both (21%).After 1-year follow-up, 13 deaths were registered of which 7 hadpositive CMV infection. The univariate analysis showed no relation-ship between positive CMV viremia and acute rejection (OR, 1.576;95% CI: 0.868–2.863; P = 0.135).

Ganciclovir prophylaxis was assessed in a randomised, double-blind, placebo-controlled study, with the impact of prophylaxis ontransplant atherosclerosis evaluated in a post hoc analysis [89]. Intotal, 149 patients were randomised to receive intravenous ganciclo-vir (5 mg/kg every 12 h for 14 days, followed by 6 mg/kg on 10 of thenext 14 days) or placebo during the first 28 days after surgery. Of




these, 121 patients who survived beyond 1 year were included in theanalysis. The actuarial incidence of transplant coronary artery dis-ease at follow-up was 43% ± 8% in ganciclovir-treated patientscompared with 60% ± 11% in the placebo arm (P b 0.1). The inci-dence of death or re-transplantation did not differ between the twotreatment arms (ganciclovir, 22% ± 3%; placebo, 17% ± 5%).

In a prospective cohort study, 66 at-risk heart transplant reci-pients received a standard or aggressive prophylactic regimen de-pending on risk [90]. Intermediate-risk (R+) patients (n = 45)received intravenous ganciclovir 5 mg/kg b.i.d. for 2 weeks aftersurgery followed by 6 mg/kg/day for the next 2 weeks. High-risk(D+/R−) patients (n = 21) received the standard protocol followedby valganciclovir (450–900 mg/day) for a total combined prophylaxisduration of 73 ± 12 days. High-risk patients also received 150 mg/kgintravenous CMV immunoglobulin at 72 h after transplantation, then100 mg/kg at weeks 2, 4, 6, and 50 mg/kg at weeks 12 and 16. Duringthe first month, when all patients received prophylaxis, acute re-jection did not differ significantly between the regimens. Duringmonths 2–6, however, the incidence of acute rejection increased inthe standard prophylaxis arm (p = 0.03 vs. aggressive prophylaxis).Overall, time to acute rejection was prolonged in the aggressive pro-phylaxis arm, which was statistically significant at 6 months afterganciclovir discontinuation (p = 0.03). Patients who received ag-gressive prophylaxis also had numerically lower serum glucose(107 ± 30 vs. 121 ± 53 mg/dL) and creatinine (1.44 ± 0.65 vs.1.86 ± 1.35 mg/dL) levels. In a subset of patients with paired base-line and follow-up intravascular ultrasound (IVUS) measurements(n = 28), vessel and lumen volumes decreased significantly in thestandard prophylaxis arm (–126 ± 111 and –140 ± 106 mm3 re-spectively; p b 0.01), but remained unchanged in the aggressiveprophylaxis arm (–28 ± 122 and –61 ± 96 mm3 respectively;p ≥ 0.1).

A longitudinal observational study in 40 patients who receivedpre-emptive CMV treatment (n = 21) or prophylaxis (n = 19) wascarried out to evaluate the development of allograft vasculopathy[91]. Prophylaxis consisted of oral valganciclovir 450 mg b.i.d. startedin the first week after transplantation and continued for 40 days.Patients positive for CMV DNA after prophylaxis received additionaltreatment with valganciclovir 900 mg b.i.d. until cleared. Maximalintimal thickening (MIT) increased significantly during follow-up inboth treatment arms, but the increase in the pre-emptive arm wasapproximately double that in the prophylaxis arm. Intimal volumeincreased significantly by ~ 20% in the pre-emptive arm, comparedwith a non-significant 5% increase in the prophylaxis arm. In addi-tion, vessel volume tended to increase in the pre-emptive arm anddecrease in the prophylaxis arm. The percentage of patients with MITchange ≥ 0.3 mm was significantly greater in the pre-emptive arm(43%) than in the prophylaxis arm (10%; p = 0.03), while 19% ofpatients in the pre-emptive arm showed an MIT change of ≥ 0.5 mmcompared with none in the prophylaxis arm. The only majordrug-related adverse event reported in the prophylaxis group was acase of leukopenia requiring treatment with granulocyte colony-stimulating factor.

3.4. Lung transplantation

In lung or heart–lung transplant recipients, analysis of the CTSdata showed that CMV prophylaxis was significantly associated witha superior 3-year graft survival in D+/R− patients (RR, 0.53;p b 0.0001).While there was a numerically lower incidence of treatedrejection episodes in patients who received prophylaxis (42.1% vs.64.3%), the difference was not statistically significant [81].

A systematic review by Sharples et al. [2002] which assessed riskfactors for the onset of BO or BO syndrome (BOS) in lung transplantrecipients [92] identified three studies that reported reductions in theincidence of BOS as a result of lower CMV event rates in patients who


had received ganciclovir prophylaxis [63,93,94]. In spite of this, thereview found little evidence that CMV infection itself is a risk factorfor BO or BOS, although the evidence for CMV pneumonitis wassomewhat stronger.

Subsequently, evidence for and against an association betweenCMV infection and BO/BOS has been published. A prospective cohortstudy in 23 lung transplant recipients found a significant positiveassociation between CMV viraemia in the first 6 months post-trans-plant and the development of BOS in univariate analysis (p = 0.002)[61]. In the first 6 months post-transplant, eight patients had CMVpneumonitis despite the ganciclovir prophylaxis, and at medianfollow-up (37 months), ten patients had developed BOS. A secondprospective cohort study by Manuel et al. [2009], however, producedcontrary results [95]. In 93 lung transplant recipients followed upfor amedian duration of ~ 25 months, acute rejection episodes (grade2 or more) affected 43 patients (46.2%), and 18 (19.4%) developedBO or BOS. Many of the patients had CMV infections (48 in bron-choalveolar lavage samples and 33 with viraemia), five had CMVpneumonitis, and seven had CMV viral syndrome. Nevertheless,CMV infection itself was not associated with BO or BOS develop-ment [95]. All patients in the two studies just described receivedprophylaxis with ganciclovir or valganciclovir, with or without CMVhyperimmune globulin (CMV Ig), but the studies did not feature acontrol group.

Four studies that did include control arms all suggest a beneficialeffect of CMV prophylactic regimens after lung transplantation,although no randomized study has yet been done to confirm theseresults. In a retrospective cohort study, 68 high-risk lung transplantrecipients (all D+) were treated with ganciclovir or valganciclovirfor 100 days post-transplant [96]; 38 patients (test group) alsoreceived CMV Ig and 30 (controls) did not. During follow-up(23.8 months for the test group and 16.5 months for controls), signi-ficantly fewer patients in the test group (13.2% vs. 43.3%; p = 0.007)developed CMV disease (typically pneumonitis), and the death ratewas also lower in the test group (0% vs. 16.7%, p = 0.014). Moreover,more test patients were free from BOS at 1 and 3 years (91.0% vs.69.7% and 82.0% vs. 54.3%, respectively; p = 0.024), although nosignificant difference was seen in the proportions who were free fromacute rejection (52.5% vs. 41.7% at 1 year and 49.0% and 35.8% at 3years). The 3-year survival rate was significantly better in the testgroup (71.5% vs. 40%; p = 0.013) [96]. In a smaller retrospectivestudy, 21 lung transplant recipients received combination prophy-laxis (3 weeks of ganciclovir or valganciclovir plus CMV Ig therapyfor 12 months) and 25 received aciclovir for at least 12 months(control group) [97]. Although the follow-up period is not reportedin the paper, grade 2 or 3 acute rejection episodes were lower in testpatients than control patients (6% vs. 17%; p = 0.04), as was lym-phocytic bronchitis/bronchiolitis (2% vs. 11%; p = 0.04), but no dif-ference was found in the rate of BO (5% in both groups), andreductions in CMV pneumonia did not achieve statistical significance.In logistic regression, CMV prophylaxis was significantly associatedwith reduced prevalence of acute rejection episodes (p = 0.03) [97].

Two other studies report the effects of prolonged courses ofprophylaxis. In a prospective cohort study, Chmiel et al. [2008] foundthat ganciclovir or valganciclovir given to 96 lung transplant re-cipients for a mean duration of 507 days (median 364 days) sig-nificantly reduced the cumulative incidence of CMV-related events(infection and/or disease) compared with 282 study and historicalcontrols who received no prophylaxis [98]. The cumulative inci-dence of grade 1 BOS was also found to be significantly lower in thetreated patients than in historical controls (43% and 60% respectively;p = 0.002), as was the survival rate (73% vs. 47%; p = 0.036).

A retrospective cohort study assessed the rate of CMV pneumonitisin 130 lung transplant recipients who were D+ and/or R+ for CMVand received CMV Ig therapy [99]: of these, 90 received indefiniteprophylaxis with ganciclovir (test group), and 40 had prophylaxis




withdrawn at various times for administrative or clinical reasons(controls). In the test group, whose prophylaxis lasted for threetimes longer than the control group (median duration), the rate ofCMV pneumonitis was significantly lower (3%) than in controls (37%;p b 0.001), and all episodes in the latter group happened afterganciclovir withdrawal. In a group of 21 D−/R− patients whoreceived oral aciclovir treatment only, four cases of CMV pneumonitisdeveloped. Despite the reduction in pneumonitis, no significantbenefit was gained by the test group in BOS-free survival or overallsurvival rates [99].

4. New trends in CMV infection

In recent years there has been increasing interest in immunolog-ical techniques for addressing CMV infection in transplant recipients,and these can be categorized broadly into four types: vaccination,passive immunotherapy, adoptive T-cell therapy and immune recon-stitution [100].

To date, anti-CMV vaccination has had limited success, with ameta-analysis by the Cochrane collaboration in 2007 finding thatvaccination of SOT recipients was not associated with any benefit interms of CMV infection or disease, or mortality [101]. More recently,promising results have been obtained with a vaccine against CMVglycoprotein-B with MF59 adjuvant [102], and numerous other CMVvaccines are in development [100]. Passive immunotherapy usinganti-CMV immunoglobulin, alone or in combination with antiviralmedication, was also investigated in the Cochrane meta-analysis,which concluded that there was no benefit of treatment on CMVinfection or disease, or all-cause mortality [101]. Adoptive T-celltherapy, in which CMV-specific CD8-positive T cells are transferredfrom a donor to the patient, is currently experimental, although thereis mounting anecdotal and early-phase study evidence of the poten-tial of the procedure [100]. It is, however, associated with numeroustechnical and clinical challenges that must be overcome before itwill be suitable for routine clinical practice.

Immune reconstitution is a process by which the immune systemis permitted to recover to the point where it is able to deal with theviral infection [100]. This is most frequently associated with AIDS, inwhich highly active antiretroviral therapy can reduce the risk of end-organ disease and allow discontinuation of CMV prophylaxis. Intransplant recipients, immune reconstitution involves the reductionof immunosuppressive therapy, allowing patients to recover, or deve-lop, anti-CMV immunity [100].

For the future, new treatment options for CMV are needed, givensome limitations of the existing agents [103,104]. In addition, data inpediatric transplantation, including the optimal duration of prophy-lactic therapy, are lacking [104].

5. Summary and conclusions

Indirect effects of CMV infection in SOT recipients can have seriousconsequences for patients, including an increased risk of acute orchronic rejection, as well as graft loss and death. In addition, CMVinfection may place some patients at increased risk of opportunisticinfections and post-transplant diabetes. Organ-specific effects in-clude an increased risk of cardiovascular disease in kidney trans-plant recipients and increased severity of HCV infection in liverrecipients. Appropriate prophylactic treatment can significantlyreduce the risk of CMV infection and disease in high-risk patients,leading to improvements in graft and overall outcomes. Based in a CTSanalysis of data regarding CMV prophylaxis, significant improve-ments in graft survival, particularly in the reduction of 3-year graftloss risk, were observed for kidney, heart and lung transplant reci-pients receiving CMV prophylaxis. Therefore, prophylaxis should beconsidered for all patients at risk of CMV infection and disease aftersolid organ transplantation.


Acknowledgments

The authors wish to thank Roche Farma Spain for funding andorganization of the ATOS meeting (Aula sobre Trasplantes de ÓrganosSólidos; the Solid-Organ Transplantation Working Group).

The authors declare no conflicts of interest.

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Documents

The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients