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CME

Update and Review: State-of-the-Art Management ofCytomegalovirus Infection and Disease Following ThoracicOrgan Transplantation

David R. Snydman, MD, FACP (Chairman), Ajit P. Limaye, MD, Luciano Potena, MD, PhD, and

Martin R. Zamora, MD

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Accreditation and Designation StatementThe University of Cincinnati is accredited by the Accredita-tion Council for Continuing Medical Education (ACCME) toprovide continuing medical education to physicians.

University of Cincinnati College of Medicine designatesthis educational activity for a maximum of 1.0 AMA PRACategory 1 Credit(s)™. Physicians should only claim creditcommensurate with the extent of their participation in theactivity.

Educational ObjectivesUpon completion of this activity, participants should bebetter able to:• Describe the incidence of cytomegalovirus (CMV) in-

fection and disease among heart and lung transplantrecipients

• Discuss factors associated with increased risk for CMVinfection and disease among high-risk heart and lungtransplant populations

• Describe the risk factors for, diagnostic tests for, andmechanisms of ganciclovir-resistant CMV

• Develop therapeutic protocols that use adjunctive op-tions to initiate prophylactic therapy for CMV infection

• Implement approaches to treating patients with severeCMV disease

• Explain the benefits and risks of current and emergingtherapies and their outcomes in preventing the indirecteffects of CMV

Target Audience: This activity was developed for heartand lung transplant surgeons, transplant cardiologists,pulmonologists, and other clinicians who treat patientsafter heart and lung transplantation.

Disclosure: The planning staffs at the University of Cin-innati and Rockpointe Corporation have no relevantnancial relationships to disclose.uthor Disclosures: Dr. Syndman received grant/

research support from AstraZeneca, Johnson & Johnson,

© 2011 Published by Elsevier Inc.360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 43, S1–S17 (2011)

erck; Consultant: Boehringer Ingelheim, CSL Behring,enentech, Genzyme, Millennium, Novartis, Viropharma;peakers’ Bureau: CSL Behring, Cubist Pharmaceuti-als, Merck. Dr. Limaye is a consultant for Amgen,ioRad, Roche, Vical, Viropharma; and received Grant/esearch Support: Roche, Viropharma; Speakers’ Bu-

eau: Novartis. Dr. Potena, is on the advisory board/onsultant: Novartis; Speakers’ Bureau: Hoffmann-Laoche, Novartis. Dr. Zamora is a consultant: CSL Beh-

ing; Speakers’ Bureau: CSL Behring, Roche; Advisoryoard: CSL Behring, Genzyme.

ponsorship: This activity is jointly sponsored by: Theniversity of Cincinnati and Rockpointe Corporation. Thisctivity is supported by an educational grant from CSLehring, LLC.

ff-label Statement: The contents of this activity mayontain discussions of non-approved or off-label uses ofome agents mentioned. Please consult the prescribing

nformation for full disclosure of approved uses.

From the Chief of Division of Geographic Medicine andInfectious Diseases (D.R.S.), Hospital Epidemiologist, TuftsMedical Center; Professor of Medicine and Pathology, TuftsUniversity School of Medicine, Boston, Massachusetts; Associ-ate Professor, Departments of Laboratory Medicine & MedicineUniversity of Washington (A.P.L), Seattle, Washington; AttendingPhysician, Clinical Researcher, Heart Failure and Heart Trans-plant Program, Cardiovascular Department, Academic HospitalS.Orsola-Malpighi, University of Bologna, Bologna, Italy; andProfessor of Medicine, Division of Pulmonary Sciences andCritical Care Medicine, University of Colorado at Denver Schoolof Medicine, Aurora, Colorado.

For questions regarding the content of this activity, and forreprint requests, contact Kay Weigand, University of Cincinnati,the accredited sponsor of this CME/CE activity, at UC College ofMedicine, PO Box 670556, Cincinnati, OH 45267-0556; or

weiganka@ucmail.uc.edu

0041-1345/–see front matterdoi:10.1016/j.transproceed.2011.02.069

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Update and Review: State-of-the-Art Management of CytomegalovirusInfection and Disease Following Thoracic Organ Transplantation

ABSTRACT

Purpose. Cytomegalovirus (CMV) is among the most important viral pathogens affect-ing solid organ recipients. The direct effects of CMV (eg, infection and its sequela; tissueinvasive disease) are responsible for significant morbidity and mortality. In addition, CMVis associated with numerous indirect effects, including immunomodulatory effects, acuteand chronic rejection, and opportunistic infections. Due to the potentially devastatingeffects of CMV, transplant surgeons and physicians have been challenged to fullyunderstand this infectious complication and find the best ways to prevent and treat it toensure optimal patient outcomes.Summary. Lung, heart, and heart-lung recipients are at considerably high risk of CMVinfection. Both direct and indirect effects of CMV in these populations have potentiallylethal consequences. The use of available treatment options depend on the level of risk ofeach patient population for CMV infection and disease. Those at the highest risk are CMVnegative recipients of CMV positive organs (D�/R�), followed by D�/R�, and D�/R�.More than 1 guideline exists delineating prevention and treatment options for CMV, andnew guidelines are being developed. It is hoped that new treatment algorithms will providefurther guidance to the transplantation community.

The first part describes the overall effects of CMV, both direct and indirect; risk factorsfor CMV infection and disease; methods of diagnosis; and currently available therapies forprevention and treatment. Part 2 similarly addresses antiviral-resistant CMV, summarizingincidence, risk factors, methods of diagnosis, and treatment options. Parts 3 and 4 presentcases to illustrate issues surrounding CMV in heart and lung transplantation, respectively.Part 3 discusses the possible mechanisms by which CMV can cause damage to the coronaryallograft and potential techniques of avoiding such damage, with emphasis on fosteringstrong CMV-specific immunity. Part 4 highlights the increased incidence of CMV infectionand disease among lung transplant recipients and its detrimental effect on survival. Thepossible benefits of extended-duration anti-CMV prophylaxis are explored, as are those ofcombination prophylaxis with valganciclovir and CMVIG.Conclusion. Through improved utilization of information regarding optimized antiviraltherapy for heart and lung transplant recipients to prevent and treat CMV infection anddisease and through increased understanding of clinical strategies to assess, treat, andmonitor patients at high risk for CMV recurrence and resistance, the health care team will

be able to provide the coordinated effort needed to improve patient outcomes.

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DESPITE advances in the development of antiviral medi-cations and the efficacy of preventive strategies in

imiting symptomatic disease, cytomegalovirus (CMV) stillepresents a major cause of infection following solid organransplantation, with an incidence between 8% and 50%epending on the organ transplanted. Lung, heart, and heart-

ung recipients are at considerably high risk of CMV infectionnd disease, particularly seronegative recipients of organsrom CMV-seropositive donors [donor-positive/recipient-neg-tive (D�/R�)]. The direct and indirect effects of CMVnfection can cause significant morbidity and mortality.

Clinical diagnosis and therapeutic management of CMV

re often challenging given the multiplicity of issues that can a

S2

ffect each patient. Antiviral agents, such as intravenous (IV)anciclovir and oral valganciclovir, are the gold standard for bothhe prevention and treatment of CMV infection and disease.epending on a patient’s type and degree of immunosuppressive

herapy, as well as risk level, recent guidelines recommend ainimum of 6 months of prophylaxis for lung transplant recipi-

nts. A study of valganciclovir prophylaxis in lung transplantecipients found that extending prophylaxis by an additional 9onths significantly reduced the rates of CMV infection and

isease (P � .001 for both), as well as disease severity (P � .009),ompared with standard prophylaxis (3 months).

CMV-specific immune globulin (CMVIG) has also been

pproved for the prevention of CMV disease and is often

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used in combination therapy with improved outcomes insolid organ transplant recipients. In a prospective cohortstudy, heart transplant recipients receiving aggressive CMVprophylaxis with CMVIG, ganciclovir, and valganciclovirhad a significantly reduced rate of acute rejection (P � .03),

reduced incidence of CMV infection (P � .038), andlower progression of cardiac allograft vascular disease inerms of coronary artery lumen loss (P � .05) and vesselhrinkage (P � .03) compared with patients receiving thetandard monotherapy regimen (ganciclovir). Anothertudy comparing combination therapy using CMVIG andanciclovir with ganciclovir monotherapy showed that com-ination therapy reduced the incidence of CMV infection13.2% vs 43.3%, P � .0007) and the development ofronchiolitis obliterans syndrome by 3 years posttransplan-ation (18.0% vs 45.7%, P � .024) in lung transplantecipients. A significant increase in the rate of survival (P �013) was also observed in the combination therapy group.

There is great concern regarding the increasing develop-ent and emergence of antiviral-resistant strains of CMV.ortunately, antiviral resistance is relatively uncommon and

ts prevalence varies widely by type of organ transplanted. Itppears that the occurrence of antiviral-resistant CMV isignificantly higher among thoracic organ recipients, but theate of occurrence is still low. Among lung transplantecipients, the overall incidence of resistance is between.2% and 15.2%, while the overall incidence of resistancemong heart transplant recipients is between 0.25% and.3%. In all these patients, the incidence of resistance isigher in patients with a D�/R� serostatus.It is crucial for all members of the transplant care team to

e aware of the risk factors for CMV infection, the signsnd symptoms of CMV disease, diagnostic techniques, andhe efficacy and safety data on the various agents for CMVanagement. Guidelines are currently available for the

revention and management of CMV in solid organ trans-lantation, along with an algorithm for treatment of antivi-al-resistant CMV. New guidelines are also in development.

1. CYTOMEGALOVIRUS INFECTION AND DISEASE:IMPACT, RISK FACTORS, AND MANAGEMENT

Despite advances in prevention and treatment, CMV re-mains the pathogen with the greatest impact on outcomesfollowing solid organ transplantation.1 Its effects are manyand varied (Fig 1) including inflammation, increased mor-bidity, and decreased graft and patient survival.2

The term CMV infection applies to a condition in whichhere is evidence of CMV replication whether or notymptoms are present. The term CMV disease indicatesMV infection with attributable symptoms.3 Rates of CMV

infection and disease among recipients of various organsare shown in Table 1.4 The three main patterns of CMVnfection are primary—new-onset infection acquired by areviously seronegative recipient of an organ from a CMV-eropositive donor (D�/R�); reactivation—latent infec-

ion reactivated in a patient who was seropositive for CMV

efore transplantation (R�), most commonly due to immu-osuppressive treatment; and superinfection, or reinfec-ion—transmission of virus from a donor to a recipient whoas seropositive for a different strain of CMV before

ransplantation (D�/R�) and additionally becomes in-ected with the donor strain.2,4

Impact of CMV

CMV can cause damage even when it is not detectable andin the absence of symptomatic disease.5 It has both directnd indirect effects, summarized in Table 2 The directffects of CMV infection, associated with high-leveliremia, have been well known for some time and manifests CMV disease, in the form of either CMV syndrome, withulike or mononucleosislike symptoms, or tissue-invasiveisease such as gastrointestinal ulcers or hepatitis. Inflam-atory pathology is most likely within the transplanted

rgan; thus, lung transplant recipients have a higher risk ofneumonitis than do recipients of other organs, whereas

iver transplant recipients are at higher risk for hepatitis.2,6

The indirect effects of CMV are postulated to result fromimmune responses in the context of prolonged low-levelviral replication. These indirect effects manifest as acceler-ated coronary atherosclerosis in heart transplant recipientsand as bronchiolitis obliterans in lung transplant recipients,both of which are forms of chronic rejection. CMV infec-tion potentiates a patient’s net state of immunosuppression,rendering the patient more vulnerable to opportunisticsuperinfection with any of several pathogens. Active CMV

Fig 1. Cytomegalovirus is the most important posttransplantpathogen.2 (Adapted with permission from Fishman JA et al. ClinTransplant. 2007;21:149-158.)

Table 1. Incidence of Cytomegalovirus in Solid OrganTransplantation4

Organ Infection Disease

Kidney 8%–32% 8%Heart 9%–35% 25%iver 22%–29% 29%ung or heart/lung 39%–41% 39%ancreas or kidney/pancreas 50% 50%

Adapted with permission from McDevitt LM. Am J Health Syst Pharm.2006;63:S3–S9.

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S4 SNYDMAN, LIMAYE, POTENA, AND ZAMORA

infection is a risk factor for development of other infectionssuch as bacteremia and invasive fungal disease, as well asfor increases in the rate of infection with other herpesvi-ruses and hepatitis C virus.2–4,7

CMV can be said to have a bidirectional association withacute graft rejection, in that the risk of developing CMVdisease is increased by the immunosuppressive drugs usedto treat rejection, as well as by the release of cytokines suchas tumor necrosis factor that may activate latent CMV. Atthe same time, CMV itself increases the risk of rejection.Several mechanisms are postulated for this effect, includingaltered expression of growth factors and cytokines, upregu-lation of proinflammatory adhesion molecules, and modu-lation of the nitric oxide synthase pathway.2,8

Risk Factors for CMV

CMV-seronegative recipients of organs from seropositive donorsare at greatest risk of developing CMV infection and disease(primary infection).

The D�/R� status is considered the greatest risk factorfor the development of CMV disease. The overall rates ofCMV infection and disease among D�/R� solid organransplant recipients are 68% and 56%, respectively.4 Theisk of CMV infection is considered moderate for D�/R�

and D�/R� patients, whereas D�/R� patients are atlower risk for CMV. D�/R� solid organ transplant recip-ients have no preexisting CMV-specific immunity. This lackof immunity is exacerbated by the use of immunosuppres-sive therapy, especially induction therapy with lymphocyte-depleting drugs and intense maintenance immunosuppres-sion, such as with triple-drug regimens.1,3

The risk of CMV infection and disease also varies withthe organ transplanted. Recipients of lung, small-bowel,pancreas, and combined kidney-pancreas transplants are athighest risk, with liver and heart recipients at intermediaterisk and recipients of kidney transplants at lowest risk.9,10

A pivotal 1997 report established an association betweenCMV viral load and the probability of a patient’s developing

Table 2. Effects of Cytomegalovirus2,6

Direct Indirect

CMV syndromeFlulike, mononucleosislike

symptomsNeutropenia

MyelosuppressionPneumonitisGastrointestinal invasionHepatitisPancreatitisChorioretinitis

Increased incidence of graftrejection

AcuteChronic

Secondary fungal, bacterial, andviral infections

Increased risk of PTLDDevelopment of cancerDecreased graft and patient

survivalUpregulation of HHV-6, HHV-7,

HCV

PTLD, posttransplant lymphoproliferative disorder; HHV, human herpesvirus;HCV, hepatitis C virus.

symptomatic CMV disease (Fig 2).11 In this study, increasing

viral load was shown in both univariate and multivariateanalyses to be an independent predictor of increased risk ofdisease following solid organ transplantation.11

Diagnosis of CMV

Several methods of diagnosing CMV are available, includ-ing antigenemia assays, nucleic acid amplification and hy-bridization, and antiviral susceptibility testing. Recent ad-vances in diagnostic techniques have produced increasinglysensitive, specific, and reliable tests, some of which yieldresults more rapidly than do conventional methods.12 An-iviral susceptibility testing, in particular, has facilitatedore effective use of preemptive antiviral therapy. Unfor-

unately, there remains a great deal of variability betweenransplant centers and between assays, so that it is difficulto identify specific thresholds for treatment or prediction ofrogression.3 Uniform, international standardization of di-gnostic tests is needed.

CMV Prevention and Treatment

The task of selecting appropriate strategies and therapiesfor prevention and treatment of CMV infection and diseaseis complicated by numerous factors, as discussed through-out this supplement. Thus, there has been a strong need forinternational, authoritative, consensus-based guidelines.Fortunately, such guidelines have now been published andare available for clinicians to use in planning patientcare.3,13

The two major approaches to CMV prevention areprophylaxis and preemptive treatment. Prophylaxis can befurther categorized as universal or targeted. With universalprophylaxis, all at-risk patients receive antiviral therapy fora defined period posttransplantation. With targeted orselective prophylaxis, patients whose clinical circumstances,such as administration of lymphocyte-depleting inductionimmunosuppression, are considered at high risk and receiveprophylactic therapy. Preemptive therapy entails monitor-ing patients regularly and administering antiviral drugs tothose with laboratory evidence of CMV replication to

Fig 2. Association between cytomegalovirus viral load anddisease probability.11 (Adapted with permission from Cope AVt al. J Infect Dis. 1997;176:1484-1490.)

prevent the development of symptomatic CMV disease.14,15

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STATE-OF-THE-ART MANAGEMENT S5

The controversy regarding which of the two major strat-egies is superior has been ongoing for decades; nonetheless,there have been very few head-to-head comparisons of thetwo strategies, and each has advantages and disadvan-tages.13,15

The advantages of universal prophylaxis include itsproven efficacy in preventing CMV disease, with rates ofprevention ranging between 58% and 80%.1 In the absence

f head-to-head trials, several meta-analyses have pooledhe results of individual trials. These analyses show thatrophylaxis prevents the direct effects and some indirectffects of CMV infection. Prophylaxis has been shown toeduce the risk of infection with other pathogens, includingther herpesviruses.1,16 Prophylaxis has also been shown to

ncrease the odds of graft survival (Fig 3) and reduce overallatient mortality, largely because of a reduction in CMV-elated mortality.1,17 The logistics of prophylaxis are sim-

pler than those of preemptive therapy, eliminating the needfor time-consuming and costly monitoring.13,15

Higher drug costs of prophylaxis and the potential sideeffects of antiviral therapy are among the disadvantages ofthis approach. The primary disadvantage of prophylaxisinvolves concern regarding a possible increase in the poten-tial for development of antiviral-resistant CMV strains.Additionally, prophylaxis may delay the development ofCMV immunity in patients, opening the door to late-onsetCMV disease.13,15

Obviously, the increased risks of drug toxicity and resis-tance with prophylaxis are reduced with preemptive ther-apy. Additionally, although the costs of monitoring are highwith this strategy, drug costs are lower than with prophy-laxis. The preemptive approach, however, is logisticallycomplex and requires strict patient adherence to a moni-toring schedule and the use of sufficiently predictive tests.Even with careful monitoring, the danger exists with thepreemptive approach that CMV may not be identified nortreatment begun early enough to prevent the developmentof symptoms.13,15 Because of these differences, the majority

Fig 3. Graft survival with cytomegalovirus prophylaxis, D�/R-heart transplant recipients.17 (Reprinted with permission fromOpelz G et al. Am J Transplant. 2004;4:928-936.)

of members of an international consensus panel, in their

recently published guidelines, favored universal prophylaxisover preemptive treatment for D�/R� transplant recipi-ents.13

Although each of the two approaches has costs associatedwith it that are considered among its disadvantages, it hasbeen shown that the costs are similar between the twomethods. A 2006 study by Khoury and colleagues comparedexpenses associated with both strategies. The mean totalcost per patient was $7130 � 3748 in the preemptive arm,ompared with $7678 � 6486 in the prophylaxis arm, aonsignificant difference.18

The possibility of delayed- or late-onset CMV disease isa concern for both members of the transplant team andtheir patients. Late-onset CMV disease typically occursbetween 3 and 6 months posttransplantation among pa-tients receiving 3 months of prophylaxis. The incidence isestimated to range between 17% and 37% among D�/R�solid organ transplant recipients.3 One strategy that hasbeen considered for prevention of late-onset disease is theuse of preemptive therapy after prophylaxis has beencompleted, but this proved to be logistically complex, andpatient adherence was low.1

The optimal duration of prophylaxis has also been asubject of ongoing debate, and it has been suggested thatprolonged prophylaxis, especially for D�/R� patients,might reduce the risk of late-onset CMV disease.1 Onelarge, international study, the Improved Protection AgainstCytomegalovirus in Transplant (IMPACT) trial, comparedthe outcomes of D�/R� kidney transplant recipients re-ceiving valganciclovir prophylaxis for 100 days (n � 164) or200 days (n � 156) posttransplantation. The incidence ofboth CMV disease and viremia was lower in the 200-daygroup than in the 100-day group (Fig 4 and 5). Theincidence of opportunistic infections at 12 months post-transplantation was also significantly lower in the 200-daygroup (12.9% vs 27.0%; P � .001), whereas the incidence ofadverse events was similar between the two groups, and thenumber of CMV-related hospitalizations was lower in the

Fig 4. IMPACT: Time to CMV disease (Kaplan-Meier curve).19

(Adapted with permission from Humar A et al. Am J Transplant.2010;10:1228-1237.)

200-day group.19

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S6 SNYDMAN, LIMAYE, POTENA, AND ZAMORA

To date, only one study comparing prolonged prophylaxiswith standard-duration treatment has been completed inthe thoracic organ transplant population. This study, in lungtransplantation, found lower rates of CMV infection, syn-drome, and disease with extended valganciclovir prophy-laxis than with a standard regimen.20 Although this issuehas not been settled definitively, the recent guidelinesrecommend a duration of prophylaxis between 3 and 6months, determined by each patient’s degree and type ofimmunosuppression and risk level, with a minimum of 6months for lung transplant recipients.13

Antiviral Drugs

The antiviral drugs available for prevention and treatment ofCMV include the CMV DNA polymerase inhibitors, ganci-clovir—both oral and IV—and its oral prodrug valganciclovir,which are currently the treatments of choice for prevention ofCMV. Valacyclovir, the prodrug of acyclovir, has been effec-tive in preventing CMV disease, but it appears to be lesseffective than either ganciclovir or valganciclovir.16 Althoughalacyclovir is approved for prevention of CMV disease inidney and heart transplant recipients, its safety and efficacyave not been established among recipients of other organs,or is it indicated for treatment of established CMV disease.21

Valganciclovir (or IV ganciclovir for patients who cannot takeoral drugs, those whose absorption of valganciclovir is subop-timal, children, and those with life- or sight-threatening dis-ease) is the recommended first-line treatment for establishedCMV disease. Oral ganciclovir, acyclovir, and valacyclovir arenot recommended for treatment of established CMV disease.Whether for prevention or treatment, antivirals should beadministered at appropriate dosages. Lower dosages may notbe effective and may promote the emergence of resistance.13

Foscarnet and cidofovir may be used to treat ganciclovir-resistant CMV disease, but they are both associated withhigh levels of nephrotoxicity that argues against theirfirst-line use for patients already taking drugs that mightaffect their renal function.16 IV CMVIG has been used in

Fig 5. IMPACT: Time to viremia (Kaplan-Meier curve).19

(Adapted with permission from Humar A et al. Am J Transplant.2010;10:1228-1237.)

prevention of CMV disease, and it is approved for this

se.22 The new guidelines offer the option of adding it toantiviral prophylaxis for thoracic organ transplant recipi-ents.13 Evidence indicates a lower CMV-related mortalityrate when CMVIG is used, as discussed below. Results of invitro studies of the experimental drug maribavir seemedpromising, but a recent phase 3 study in hematopoietic stemcell transplantation indicated that maribavir at the dosagechosen may not be effective in preventing CMV disease. Asa result of these findings, a phase 3 study of maribavir insolid organ transplantation was discontinued.1 For bothheart and lung transplant recipients, the recently publishedinternational consensus guidelines recommend prophylaxiswith either valganciclovir or ganciclovir (oral or IV), with orwithout CMVIG.13

There have been relatively few well-designed, controlledtrials of the use of passive immunization with CMVIG forprevention of CMV infection and disease. A meta-analysisof prospective, randomized trials compared CMVIG withno treatment or with other antivirals for prevention ofCMV infection and disease in solid organ transplant recip-ients. CMVIG reduced all-cause and CMV-related mortal-ity, as well as the incidence of CMV disease, but not that ofCMV infection or graft rejection.23 Recently, another studynalyzed data from the Scientific Registry of Transplantecipients regarding heart transplant recipients who had

eceived CMVIG (n � 2112), other antivirals with noMVIG (n � 12,089), or no antiviral (n � 14,661) between995 and 2008; CMVIG was associated with significantlyncreased patient and graft survival at 7 years post-trans-lantation (P � .001 for both).24 Studies of kidney and liver

transplant recipients in the Registry yielded similar re-sults.25–27 Another study looked at the effects, at 7 yearsfter kidney transplantation, of CMVIG at discharge withhose of no antiviral treatment among D�/R� organecipients. In a multivariate model, CMVIG was indepen-ently associated with a 21% lower risk of graft loss (hazardatio, 0.79; P � .01) and a trend toward greater survival

(hazard ratio, 0.83; P � .073).25 The current guidelinesacknowledge that data are limited for the use of CMVIGalone for prophylaxis and that some centers use it inconjunction with antivirals, particularly in the thoracictransplant population.13

Treatment of Established CMV Disease

IV ganciclovir has been the gold standard of treatment forCMV disease for several years. Recently, however, valgan-ciclovir has emerged as an oral treatment option with thepotential for efficacy equivalent to that of IV ganciclovirbecause of its superior bioavailability to that of oral ganci-clovir.1,13 The Valcyte in CMV-disease Treatment of solidOrgan Recipients (VICTOR) trial randomized 321 solidorgan transplant recipients with CMV disease to undergotreatment with either IV ganciclovir or oral valganciclovir.28

In regard to both timing of viral eradication and clinicalsuccess, valganciclovir demonstrated noniferiority to IVganciclovir. Results were consistent between the intent-to-

treat and per-protocol populations, and there were no

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STATE-OF-THE-ART MANAGEMENT S7

major between-group differences in types or frequencies ofadverse events.28 The availability of a once-daily oral drug

ith equivalent efficacy to that of IV ganciclovir offersdvantages in terms of logistics and ease of administrationhat are likely to enhance patient adherence to prophy-axis.29

Relapse/Recurrence After Treatment

Relapse/recurrence of CMV disease, especially gastrointes-tinal CMV disease, after treatment is not uncommonamong solid organ transplant recipients, even among thosewith documented undetectable viral load. The estimatedrate ranges between 15% and 35% across organs.15 In aecent study, 27% of solid organ transplant recipients hadvidence of relapsing CMV viremia or disease withinpproximately 2 1/2 years following completion of treat-ent for CMV disease.30 In this study, only the extent of

initial CMV disease was significantly associated with in-creased risk of relapse (P � .03). Other risk factors havebeen identified, including D�/R� serostatus, multisystemdisease, and treatment for rejection.15

Most recurrence is a result of incomplete suppression ofviral replication rather than of emerging drug resistance. Ithas been estimated that complete viral eradication occurs inonly about 58% of patients with 21 days of treatment withIV ganciclovir, despite symptomatic resolution, suggestingthat prolonged therapy may be helpful. Some centers usesecondary prophylaxis following treatment completion toprevent recurrence of disease. If secondary prophylaxis isused, oral valganciclovir is recommended, and viral loadsshould be monitored for the possible emergence of resis-tance.15,28

2. ANTIVIRAL-RESISTANT CYTOMEGALOVIRUS:RECOGNITION AND TREATMENT

The potential for antiviral-resistant CMV has been increas-ingly recognized in the era of potent immunosuppressioncombined with longer and more intensive antiviral strat-egies. Fortunately, antiviral resistance is relatively un-common, but it carries with it the potential for significantmorbidity and mortality when it is present. Although theterm antiviral resistance is used in this article, from aclinical perspective, the majority of antiviral resistance isspecifically ganciclovir resistance rather than resistanceto other licensed anti-CMV drugs (cidofovir, foscarnet).Antiviral resistance in this article will refer to ganciclovirresistance unless otherwise specified. This is particularlyrelevant, as ganciclovir is the primary antiviral used forboth prevention and treatment of CMV infection anddisease following solid organ transplantation.

Incidence of Antiviral-Resistant CMV

The incidence of antiviral-resistant CMV varies widely byorgan and is apparently significantly higher among recipi-ents of thoracic organs than among recipients of abdominal

organs. The overall incidence of resistance among lung

ransplant recipients has been observed to range between.2% and 15.2%,31–33 and the incidence among D�/R�

lung transplant recipients ranges between 10.5% and27%.32,33 Among heart transplant recipients, the observedincidence of resistance ranges between 0.25% and 5.3%overall, with an incidence ranging between 1.4% and 5%among D�/R� heart transplant recipients.33–35

Several aspects of antiviral resistance appear to be dif-ferent in the lung transplant population than in othertransplant populations. For example, although antiviral-resistant CMV develops almost exclusively in other solidorgan transplant recipients with D�/R� CMV serostatus,in lung transplantation it also has been observed in R�recipients.31,32 Also, some lung transplant recipients havebeen observed to develop resistance after a relatively shortduration of ganciclovir exposure.31,36 The high rates ofntiviral-resistant CMV seen among lung transplant recip-ents might be related to the relatively high intensity ofmmunosuppression used in this setting and the fact that theung is a major site of CMV latency. It is hypothesized thatesistant mutants could be selected from high viral loads inhe context of impaired CMV-specific immunity and pro-onged antiviral drug exposure.32

A majority of the data regarding antiviral-resistant CMVwere generated in an era during which oral ganciclovir was themost-used prophylactic agent. It has been proposed thatprophylaxis with valganciclovir, which offers superior bioavail-ability to that of oral ganciclovir, might more effectivelyprevent subclinical infection and, thus, result in a lowerincidence of resistance. Indeed, a subanalysis of a large studycomparing valganciclovir with oral ganciclovir showed a lowerrate of resistance among patients given valganciclovir, partic-ularly among those with suspected CMV disease.29

Caveat: Not all resistance necessarily results in clinical failure,and not all clinical or virologic failure is necessarily due toresistance.

Risk Factors for Antiviral-Resistant CMV

As is true for the overall risk of CMV infection/disease,D�/R� serostatus is one of the major risk factors for thedevelopment of antiviral-resistant CMV. Additionally, ahigh viral load, prolonged and perhaps incompletely sup-pressive antiviral exposure, and the use of potent immuno-suppression are all factors that might facilitate the emer-gence of resistance.32,37

Specific mutations in the CMV genome have been shown toconfer phenotypic resistance to ganciclovir. Ganciclovir, afteruptake within CMV-infected cells, is initially phosphorylatedby a CMV protein kinase encoded by UL97. The monophos-phorylated form is then converted through two additionalphosphorylation steps (mediated by cellular kinases) into itsactive form. The active triphosphorylated form of ganciclovirinhibits CMV DNA polymerase (encoded by the CMV regionUL54) (Fig 6).3,35 UL97 and UL54 are the two primary

regions in which mutations can occur that confer ganciclovir

S8 SNYDMAN, LIMAYE, POTENA, AND ZAMORA

resistance, with mutations in UL97 being the most commonmechanism of resistance.3,37,38

As shown in Fig 7, mutations (amino acid substitutionsand/or deletions) at codons 460, 520, and 590–607 are the“hot spots” where specific mutations have been shown toconfer more than 90% of ganciclovir resistance,13,37 withthree specific codons—460, 594, and 595— accounting forabout 70% of clinical ganciclovir-resistant CMV strains.39

Mutations in the UL97 region do not confer cross-resis-tance to other available antivirals.33

Mutations in the UL54 region are much less commonthan in the UL97 region but can variably confer resistanceto foscarnet or cidofovir in addition to ganciclovir. Muta-tions in the UL54 region usually occur as second-stepmutations in strains that have already developed UL97mutations (Table 3).37 These mutations tend to be associ-

Fig 6. Ganciclovir Mechanism of Action.35 (Adapted with per-mission from Limaye AP. Clin Infect Dis. 2002;35:866-872.)

ated with higher-grade ganciclovir resistance than are UL97mutations.13,38,40

Diagnosis of Antiviral-Resistant CMV

Laboratory confirmation of antiviral resistance often takesseveral days. Thus, at least initially, resistance must besuspected on clinical grounds pending confirmation vialaboratory testing. Clinical scenarios in which resistancemight be suspected include failure to mount a clinicaland/or virologic response after 2 weeks of full-dose ganci-clovir therapy, especially among patients with cumulativeganciclovir exposure exceeding 6 weeks.13

The preferred diagnostic test for antiviral resistance isthe detection of resistance-conferring mutations directly inclinical samples (eg, plasma, bronchoalveolar lavage, cerebro-spinal fluid). Regions of the CMV genome that are known tocontain resistance-conferring mutations are amplified, and thesequence is compared to established (susceptible) laboratorystrains. Such tests rely on the demonstrated association be-tween phenotypic resistance and specific mutations in UL97and UL54.13,37 The map in Fig 8 shows that the areas in the

Fig 7. CMV phosphotransfer-

Table 3. Antiviral Resistance: Genotype/PhenotypeCorrelations37

Mutation Codon Range

Drug Resistance

Ganciclovir Cidofovir Foscarnet

UL97 460–607 � � �

UL54 301–545 � � �

588–787 � � �

802–821 � (low) � �

981–982 � � �

ase (UL97) map.

lorgg

STATE-OF-THE-ART MANAGEMENT S9

UL54 region that can confer resistance are significantlybroader than in UL97; therefore, it is technically moredifficult to develop assays for mutations that confer resis-tance in UL54.37

Treatment of Antiviral-Resistant CMV

There are few alternative treatment options for patientswith antiviral-resistant CMV, but having data on precisemutations can help guide antiviral treatment selection forpatients in whom ganciclovir has failed. Most data are fromobservational studies or case series rather than from con-trolled trials; treatment must be based on clinical suspicionand depends on host factors (degree of immunosuppres-sion, serostatus), viral factors (cross-resistance), clinicalfactors (disease severity), and prior antiviral drug expo-sure.13,39

The authors of the recently published international con-sensus guidelines offer an algorithm for treatment of anti-viral-resistant CMV (Fig 9).13 They suggest that for patientswith life-threatening or sight-threatening CMV disease,foscarnet should be added to ganciclovir while one awaitsgenotypic assay results. The algorithm is more complex,with more options for patients without life-threateningdisease; choices may include a higher ganciclovir dosage,the addition of CMV immune globulin, a reduction orchange in the immunosuppressive protocol, alternativeantiviral drugs, or experimental agents such as leflunomideor maribavir. Although trials of the latter agent werediscontinued when it was found no more effective thanplacebo, it has been used as salvage therapy for multidrug-resistant CMV, as it shows no evidence of cross-resistancewith currently used antiviral drugs. Because the likelihood

Fig 8. CMV DNA polymerase(UL54) mutation map.40 (Reprintedwith permission from Chou S et al.J Infect Dis. 2003;188:32-39.)

of cross-resistance to cidofovir in ganciclovir-resistant iso-

ates is relatively high and because clinical data with the usef cidofovir in this setting are limited, the panel does notecommend empirically switching patients with suspectedanciclovir-resistant CMV to cidofovir unless and untilenotypic data confirm cidofovir susceptibility.13

Several other alternative agents are currently undergoingstudy or have been used in small numbers of patients aspotential treatments for antiviral-resistant CMV, eitheralone or in combination with other interventions. Theseinclude the target of rapamycin inhibitors sirolimus andeverolimus, which have been observed to be associated witha lower incidence of CMV; CMX-001, an ester formulationof cidofovir that is reported to have less toxicity; lefluno-mide; and artemether compounds.1,13

3. CYTOMEGALOVIRUS INFECTION AND DISEASE INHEART TRANSPLANTATION

Despite advances in antiviral medication developmentand the efficacy of preventive strategies in limiting symp-tomatic disease, CMV still represents a major cause ofinfection following solid organ transplantation.2 Thecomplex interplay between host immune system, viralreplication, and immunosuppressive burden may result ina wide variety of graft-related or systemic syndromesassociated with CMV replication. Clinical diagnosis andtherapeutic management of CMV are often challenginggiven the multiplicity of issues that can affect eachpatient. The aim of this section is to improve awarenessof the impact of CMV infection and its sequelae onoutcomes for heart transplant recipients and identifytools for an anti-CMV approach tailored to individualpatient features. The following case study illustrates

some of these issues clinically.

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S10 SNYDMAN, LIMAYE, POTENA, AND ZAMORA

Case Study

The patient is a 30-year-old woman with D�/R CMV serostatuswho underwent heart transplantation followed by 90 days ofvalganciclovir prophylaxis. The first year posttransplantation wasuneventful, and she experienced no rejection. One month followingher 1-year visit, the patient returned to the clinic with progressive-onset shortness of breath; mitral and tricuspid regurgitation and a25% left ventricular ejection fraction were found. Biopsy revealedgrade 1R rejection (formerly 1B); graft-specific anti-HLA antibod-ies were seen in her blood, leading to a diagnosis of antibody-mediated acute rejection.

The patient was treated with plasmapheresis, intravenous immuno-globulin, rituximab, and corticosteroids, and she slowly recovered herleft ventricular function. Three weeks later, she had a sudden drop inwhite blood cell count and developed a low-grade fever. CMVinfection was suspected, and, indeed, a high grade of CMV DNAcopies was found on whole-blood polymerase chain reaction (PCR).The patient was started on IV ganciclovir 5 mg/kg BID, but after a fewdays was forced to stop the ganciclovir because of bone marrowtoxicity (white blood cell count �2000/mm3). The patient was theniven recombinant granulocyte colony-stimulating factor and CMVIG50 mg/kg for 5 days, after which we observed an increase in white

Fig 9. Proposed algorithm for treatment of antiviral-resistant cransplantation. 2010;89:779-795.)

lood cell count and a decrease in CMV load. We then reinstituted a

he IV ganciclovir. CMV load decreased significantly on PCR, and theull ganciclovir course was completed safely.

Although both prophylactic and preemptive strategies effectivelyrevent CMV disease (with additional benefits observed withrophylaxis),41 monitoring with sensitive assays such as DNA PCRr pp65 antigenemia reveals that a majority of heart transplantecipients will develop CMV infection, with only a delay of onsetmong patients who receive prophylaxis.42,43 Whereas historicaltudies found that CMV disease is associated with cardiac allograftasculopathy (CAV) and with reduced survival,44 several more-

recent clinical and experimental observations support the conceptthat CMV infection may lead to adverse graft-related conse-quences, regardless of its clinical appearance. In kidney transplan-tation, for example, a pivotal study showed that subclinical CMVinfection, as detected by pp65 antigenemia, was associated with asignificant increase in the risk of overall mortality (P � .001).45

In the heart transplant setting, our group showed that amongrecipients treated with a preemptive strategy, asymptomatic CMVinfection was associated with increased risk of developing CAVdefined as abnormal coronary remodeling 1 year after transplan-tation.46 In a recent retrospective study of more than 700 heartransplant recipients, Patel and colleagues found that patients with

egalovirus.13 (Reprinted with permission from Kotton CN et al.

ytom

symptomatic infection developed transplant coronary artery dis-

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STATE-OF-THE-ART MANAGEMENT S11

ease at a similar rate to that of patients with symptomatic CMVinfection, and both groups had significantly worse prognoses thandid patients with no CMV infection (P � .020).47 These findingsuggest that therapeutic strategies designed to minimize CMVeplication after transplantation may provide a prognostic benefit.

Possible Mechanisms of CMV Coronary Damage

CMV may affect vascular injury via inflammation and immuneevasion.

CMV drives a complex interaction with the host, triggeringimmune-evasion mechanisms and proinflammatory pathwaysand ultimately leading to endothelial cell injury and develop-ment of CAV.48 Interaction of CMV with the host inflamma-ory response sets the stage for viral replication and activeMV infection. Viral glycoprotein B-mediated virion entrynd interaction with host leukocyte toll-like receptors leads toctivation of the transcription factor NF�B, required for CMVranscription. This interaction is thought to contribute to theevelopment of atherosclerosis.49,50

The activation of proinflammatory cytokines and chemo-kines by cellular or viral-encoded genes facilitates migrationof inflammatory cells to the sites of chemokine productionand stimulates smooth muscle cell proliferation, eventuallyleading to development of intimal hyperplasia, the majorfeature of CAV. Of note, the association between CMVinfection and allograft damage depends on the presence ofan immune response against the graft.48 Cook and col-eagues showed that latent CMV infection is associated withisruption of allograft tolerance and with intramyocardialranscription of proinflammatory genes in allografts but notn isografts.51

In addition to proinflammatory effects, CMV activatesimmune-evasion mechanisms and is able to affect hostimmune response negatively. An example of this was shownin a series of experiments in which circulating dendritic cellsfrom heart transplant recipients with subclinical CMVinfection displayed an immature phenotype and a reducedability to present antigens compared with dendritic cellsisolated from heart transplant recipients without CMVinfection.52 The impact of CMV on the immune system isrelevant not only to control CMV replication, as shown instudies analyzing CMV-specific T cell response,53,54 butlso to control the risk of CAV development. In a series ofMV-seropositive heart transplant recipients receiving pro-hylaxis, Tu and colleagues showed that those with delayedeconstitution of CMV-specific T cell response also devel-ped coronary lumen loss, in contrast to those with earlyMV-specific immunity.53 Such studies provide evidence of

mechanisms supporting clinical observations linking sub-clinical CMV infection to subsequent allograft damage.

Prevention of CMV in Heart Transplantation

As discussed in Part 1 of this supplement, two strategies arecommonly used for prevention of CMV infection anddisease: universal prophylaxis and preemptive therapy.

Whereas prophylaxis effectively suppresses viral replication

uring the first weeks/months after transplantation whenhe burden of immunosuppression is higher, the preemptivetrategy permits early low-grade viral replication in theelief that it may stimulate the host’s own immune responsegainst the virus and reduce patients’ need for antiviralrugs.13,55

A key issue in selecting the optimal strategy for preven-tion of CMV infection and disease is the choice to limit orto allow asymptomatic CMV replication. A recent random-ized study in kidney transplantation showed longer graftsurvival among patients receiving prophylaxis than amongthose treated with a preemptive approach.5 Similarly, in anonrandomized study in heart transplantation, our groupfound that an aggressive anti-CMV approach—based onvalganciclovir prophylaxis followed by CMV monitoringand adjunctive treatment if significant reactivation ap-peared—is associated with delayed CMV onset, reducedoverall CMV burden, and less progression of CAV asreflected by lack of increase in year-1 intimal hyperplasia.43

In addition to antiviral drugs, new evidence regarding theanti-CMV effect of inhibitors of the mammalian target ofrapamycin (mTOR), such as sirolimus and everolimus,suggests these agents as potential strategies to limit theimpact of CMV infection on graft function. These twodrugs, approved for prevention of acute rejection, haveboth been shown to reduce the occurrence of CMV infec-tion among solid organ transplant recipients compared withtacrolimus or mycophenolate mofetil (MMF).56,57 Of note,the anti-CMV effect of mTOR inhibitors depends on theirability to inhibit cell proliferation and translation machineryand not on a direct effect on CMV proteins. Nevertheless,the magnitude of mTOR inhibitors’ actions in limitingCMV infection appears to exceed the protective effect ofvalganciclovir prophylaxis. Indeed, in a preliminary obser-vational study including patients receiving valganciclovirprophylaxis or treated with a preemptive strategy, it wasfound that those on maintenance immunosuppression reg-imens that included everolimus developed less CMV infec-tion than did those receiving MMF. Moreover, patients inboth everolimus arms displayed less CMV infection thandid patients receiving MMF and antiviral prophylaxis (Ta-ble 4).58

Immunomodulatory agents provide yet another strategyfor preventing CMV infection and reducing its effects onallograft survival. In several studies, the combination ofganciclovir with CMVIG was observed to be superior toganciclovir alone in preventing acute rejection andCAV.59–61 Although we cannot exclude the possibility thatdifferent durations of prophylaxis may be even more impor-tant, there is evidence that CMVIG can provide additionalbeneficial immune modulation of host responses, therebyreducing the risk of acute rejection.62 Moreover, modula-tion of CMV-specific cellular immunity appears to play arole in reducing mean and peak CMV loads and preventingCMV-mediated graft injury.53

One group compared standard prophylaxis (25 days of IV

ganciclovir monotherapy) with an aggressive combination

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S12 SNYDMAN, LIMAYE, POTENA, AND ZAMORA

regimen (standard IV ganciclovir) followed by maintenancewith valganciclovir (73 � 12 days) and CMVIG adminis-tered at a dose of 150 mg/kg 3 days posttransplantation andthen at 100 mg/kg at weeks 2, 4, 6, and 8 and 50 mg/kg atweeks 12 and 16 posttransplantation. It was found that theaggressive combination regimen reduced and delayed theincidence of CMV infection (Fig 10), significantly reducedthe rate of acute rejection during months 2 to 6 posttrans-plantation (Fig 11), and was associated with significantlyless loss of vessel and lumen volume and, thus, less CAV(Fig 12) than the standard regimen.59

These data support the hypothesis that interventionsdesigned to increase CMV-specific immunity (eg, develop-ment of a vaccine, use of CMVIG prophylaxis) may provideyet another strategy for protection from CMV infection andCAV. They also highlight the concept that aggressivelimitation of even subclinical CMV infection with strategiesbased on prophylaxis with antiviral agents and/or CMVIGand careful selection of the maintenance immunosuppres-sion regimen may effectively protect long-term graft func-tion.

Table 4. Effect of Immunosuppressive Regimen o

EndpointEverolimus

(n � 37)

CMV infection 44 � 8%eed for CMV treatment 19 � 7%

Prophylaxis(n � 14)

Preem(n �

MV infection 37 � 13% 48 �

eed for CMV treatment 15 � 9% 23 �

Adapted with permission from Potena L et al. Presented at: ISHLT 30th Anniv

4. CYTOMEGALOVIRUS INFECTION AND DISEASE INLUNG TRANSPLANTATION

The following case study clinically illustrates many of theissues discussed in this section.

Case Study

The patient is a 62-year-old man who underwent single-lungtransplantation for chronic obstructive pulmonary disease. HisCMV serostatus was D�/R�. Because the most recent guidelinesdo not recommend preemptive therapy for D�/R� patients, thisman underwent 180 days’ prophylaxis with oral valganciclovir plusCMVIG immediately following transplantation.

Approximately 18 months posttransplantation, he developedshortness of breath. His chest x-ray revealed diffuse pulmonaryinfiltrates in the graft and a decline of 18% in his forced expiratoryvolume in 1 second. Bronchoscopy with transbronchial biopsyrevealed CMV pneumonia. The patient received IV ganciclovir 5mg/kg BID until the PCR became negative and he was givenCMVIG 100 mg/kg per dose at four doses every 4 days, followingwhich he was maintained on 900 mg/d oral valganciclovir.

The patient made a complete recovery; however, 3 months laterhe developed a positive PCR for CMV of 25,000 copies/mL. He

tomegalovirus (CMV) in Heart Transplantation58

Mycophenolate Mofetil(n � 98) P Value

87.3% �.0160 � 5% �.01

Prophylaxis(n � 32)

Preemptive(n � 66)

78 � 7% 91 � 3% �.0140 � 9% 70 � 6% �.01

Meeting and Scientific Sessions; April 21–24, 2010; Chicago, IL. Abstract 474.

Fig 10. Combination prophylaxisreduces cytomegalovirus infec-tion.59 (Adapted with permissionfrom Potena L et al. Transplanta-

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was treated with 900 mg BID oral valganciclovir but continued tohave a CMV-positive PCR. Because possible antiviral resistancewas suspected, he was switched to IV ganciclovir 5 mg/kg BID plusCMVIG 100 mg/kg per dose every 4 days for four doses, andgenotypic testing for antiviral resistance was performed. The testwas positive for a high level of ganciclovir resistance, but there wassensitivity to both foscarnet and cidofovir. The patient was treatedwith IV foscarnet and weekly CMVIG 100 mg/kg for 6 weeks, afterwhich his PCR become negative. He has been maintained onleflunomide, with regular PCR monitoring.

Epidemiology of CMV in Lung Transplantation

Lung transplant recipients are at higher risk for CMV than arerecipients of other organs.

The incidence of CMV infection and disease is higheramong lung transplant recipients than among recipients ofother solid organ transplants, with an estimated incidenceranging between 30% and 86%.63 As is the case in trans-

lantation of most organs, the D�/R� serostatus is a

Fig 11. Combination prophylaxis reduces risk of acute rejec-tion.59 (Adapted with permission from Potena L et al. Transplan-tation. 2006;82:398-405.)

Fig 12. Combination prophylaxis reduces CAV.59 (Adapted with

permission from Potena L et al. Transplantation. 2006;82:398-405.)

primary risk factor for CMV infection among lung trans-plant recipients, followed by any R� combination (Fig13).64,65 The use of antilymphocyte antibodies as inductionimmunosuppression or to treat rejection increases theCMV risk as well, as does coinfection with other herpesvi-ruses.63

There are two risk factors unique to lung transplantation.First, the lung has been identified as a major site for CMVlatency and recurrence.66 Second, the transplanted lung isurrounded by large amounts of lymphatic tissue, which isransferred along with the lung, and thus harbors moreatent CMV than do other organs. Therefore, some expertsuggest that all lung transplant recipients be considered atigh risk for CMV infection and disease regardless oferostatus.63 Despite various prophylactic strategies of du-

rations ranging from 2 weeks to 90 days, which was consid-ered the standard of care until recently, the incidence ofCMV infection among lung transplant recipients remainshigh.

CMV, BOS, and Survival

Chronic rejection, or bronchiolitis obliterans syndrome(BOS), is associated with reduced survival among lungtransplant recipients, particularly after the first year post-transplantation.64 A retrospective chart review of lungransplant recipients from 1999 through 2009 showed thathe primary cause of death was respiratory failure second-ry to BOS (Fig 14).67

In the study just mentioned, as well as in other studies,the presence of CMV infection has been observed topredict the development of BOS (Fig 15).67,68 To somedegree, this threat has been ameliorated by the adoption ofearly anti-CMV prophylaxis, but the optimal prophylacticregimen has not been definitively identified and universallyadopted, and invasive CMV infection remains a risk factorfor the development of BOS.65

CMV Prophylaxis and Treatment in Lung Transplantation

Studies in the 1990s found that a short course of ganciclovirmonotherapy delayed but did not effectively prevent CMVinfection. Extending the duration of prophylaxis decreasedthe rate of CMV infection and disease, but only temporar-ily. The pooled results of early trials of monotherapy withIV ganciclovir for up to 90 days yielded a 59% rate of CMVinfection and a 42% rate of CMV disease.63

The advent of valganciclovir, which provides antiviral expo-sure comparable to that of IV ganciclovir and efficacy at leastas good as that of oral ganciclovir, allowed for effective,prolonged oral prophylaxis.63 A recent study compared twoourses of valganciclovir prophylaxis: 3 months of open-labelalganciclovir therapy followed by 9 additional months ofither continued valganciclovir (n � 70) or placebo (n � 66).he patients in the extended therapy group had significantly

ower rates of CMV infection (P�.001), CMV syndrome (P �004), and invasive CMV disease (P � .001) than did the

lacebo group (Fig 16).20

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S14 SNYDMAN, LIMAYE, POTENA, AND ZAMORA

Another potential improvement over ganciclovir mono-therapy is a combination of ganciclovir or valganciclovirwith CMVIG. Several studies have shown advantages ofcombination prophylaxis over monotherapy.60,69 Ruttmannnd colleagues compared the effects of ganciclovir aloneith those of a combination of ganciclovir plus CMVIGfter lung transplantation. They found that survival wasignificantly superior in the combination group (Fig 17).

Fig 13. Cytomegalovirus serostatus and survival in lung transpLung Transplant. 2009;28:1031-1049.)

Fig 14. Kaplan-Meier curve: Survival after lung transplanta-tion.67 (Adapted with permission from Parada MT et al. Trans-

plant Proc. 2010;42:331-332.) I

dditionally, the respective rates of CMV disease (13.2% vs3.3%, P � .0007) and development of BOS by 3 yearsosttransplantation (18.0% vs 45.7%, P � .024) wereuperior in the combination group to those in the mono-

tion.64 (Adapted with permission from Christie JD et al. J Heart

Fig 15. Cytomegalovirus infection predicts BOS develop-ment.68 (Reprinted with permission from Zamora MR. Transpl

lanta

nfect Dis. 2001;3:49-56.)

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STATE-OF-THE-ART MANAGEMENT S15

therapy group.61 Similarly, Weill and colleagues found asignificant reduction in overall CMV disease with combina-tion prophylaxis vs ganciclovir monotherapy (Fig 18).70

For treatment of CMV disease in lung transplant recip-ients, several centers use IV ganciclovir for 2 weeks fol-lowed by another week of ganciclovir accompanied byCMVIG. Published literature on the efficacy of this proto-col in lung transplantation is scarce, but evidence from bonemarrow transplant studies suggests that combination ther-apy might provide benefits in treatment as it does inprophylaxis.63,66

CONCLUSION

CMV infection and disease continue to be common andcause significant complications following solid organ trans-

Fig 16. Effects of prolonged cytomegalovirus prophylaxis.20

Fig 17. Kaplan-Meier analysis of survival among lung trans-lant recipients.61 (Adapted with permission from Ruttmann E

t al. Transplantation. 2006;81:1415-1420.)

lantation. CMV infection may not always manifest withbvious symptoms, making recognition of this complicationven more important, due to the significant morbidity andortality associated with CMV. Although there are effec-

ive treatments for CMV infection, prevention is preferable.he best strategy for preventing CMV infection has noteen definitively identified, although it appears that pro-hylaxis is preferred over preemptive treatment. Someatients may benefit from antiviral monotherapy, while aual-drug strategy may be more appropriate in others.here is no consensus regarding optimal duration of pro-hylaxis, but data from recent clinical trials suggest that a

onger duration of treatment may yield superior outcomes.Although antiviral resistance to CMV infection is uncom-on, it remains an important issue. It is of particular

oncern in thoracic organ recipients, as the incidence ofntiviral-resistant strains of CMV appears to be higher inhese patients than in abdominal organ recipients.

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