defining the risks for cytomegalovirus infection and disease after solid organ transplantation

Defining the Risks for Cytomegalovirus Infection andDisease After Solid Organ Transplantation

Robert J. Stratta, M.D., FACS, Carolynn Pietrangeli, Ph.D., and G. Mark Baillie, Pharm.D., M.H.A.

Cytomegalovirus continues to be one of the most clinically significantinfections after solid organ transplantation. Classic definitions of patients athigh risk for infection and tissue-invasive disease are focused on recipient-donor serostatus, type of organ transplanted, and overall level of immuno-suppression. However, recent trends in clinical practice call for a reevaluationof cytomegalovirus infection risks after solid organ transplantation. Indeed,whereas early-onset cytomegalovirus infection is usually controlled byantiviral prophylaxis with ganciclovir and derivatives, delayed- and late-onsetcytomegalovirus infection can develop after the completion of a course ofpreventive therapy. In addition, indirect effects of cytomegalovirus infectionmay occur as a result of persistent low-level viremia. Suboptimal dosing ofantiviral drugs due to specific drug toxicities may result in the development ofganciclovir-resistant cytomegalovirus disease. The relationship between organallograft rejection and cytomegalovirus infection and disease has beenrecognized for some time. Transplantation of increasing numbers ofextended-criteria donor organs increases the risk of delayed graft function andacute rejection, prompting the use of more intensive immunosuppression. Inaddition, the trend to spare long-term exposure to calcineurin inhibitors hascontributed to a resurgence in the use of polyclonal T-cell induction immuno-suppressive agents, which may reduce host anticytomegalovirus immunity.We discuss the current trends in solid organ transplantation that provide afoundation for defining risks for cytomegalovirus infection and disease,including identification of patients who would benefit from more aggressivecytomegalovirus monitoring and prevention strategies.Key Words: cytomegalovirus, solid organ transplantation, infection,immunosuppression, rejection, risk factors, serostatus.(Pharmacotherapy 2010;30(2):144–157)

OUTLINE

Natural History of Cytomegalovirus Disease AfterSolid Organ TransplantationDirect Effects of CytomegalovirusIndirect Effects of CytomegalovirusConsequences of Cytomegalovirus Infection and

DiseaseTiming of Cytomegalovirus Infection and Disease

Assessment of RiskDonor and Recipient SerostatusViral LoadAnticytomegalovirus Immunity and

Immunosuppression

Induction TherapyMaintenance ImmunosuppressionCytomegalovirus and Acute RejectionAdditional Risk Factors for Cytomegalovirus Infection

Working Definitions of High, Intermediate, and LowRisk for Cytomegalovirus Infection and Disease

Prevention of Cytomegalovirus Infection and DiseaseRedefining RiskConclusion

Despite advances in viral detection andmonitoring, regimens of antiviral prophylaxisand treatment, and our current understanding of

DEFINING RISKS FOR CYTOMEGALOVIRUS INFECTION OR DISEASE Stratta et al

infection pathogenesis, cytomegalovirus remainsone of the most clinically significant opportunisticpathogens in solid organ transplant recipients.1

Cytomegalovirus, a member of the �-herpesvirusgroup, is a ubiquitous double-stranded DNAvirus that infects humans and remains latentwithin myeloid cells and lymphoid organs forlife. Cytomegalovirus is highly cell associatedand demonstrates heterogeneity among strains.Although most cytomegalovirus infections in thegeneral population are asymptomatic, the potentialfor reactivation persists because of life-long latency.2

In immunosuppressed transplant recipients,cytomegalovirus infection may manifest as a viralsyndrome or specific organ involvement (tissue-invasive disease), or may have indirect effectsincluding graft rejection.1–3 Classically describedrisk factors for disease development after trans-plantation include donor-recipient serostatusmismatch, organ transplant type, and theimmunologic status of the recipient.

The current paradigm of immunosuppressivetherapy has shifted toward potent antibodyinduction therapies (front-loaded immuno-suppression) to provide a protective umbrella forsubsequent allograft adaptation during theconsolidation phase. These therapies directlytarget the lymphocytes involved in conferringprotective immunity against cytomegalovirusreplication. Furthermore, contemporary mainte-nance immunosuppressive regimens are morerobust than those used previously, so a trade-offof lower acute rejection rates in the current erahas been the reemergence of viral infections suchas cytomegalovirus, Epstein-Barr virus, andpolyomavirus.4, 5

Several excellent recent reviews discuss themanagement of cytomegalovirus infection anddisease in transplant recipients.1–3, 6, 7 Becauseour understanding of the unique direct andindirect virologic effects of cytomegalovirusinfection has increased, this review is dedicatedto revisiting the identification of risk factors andthe consignment of risk status, and to defining

the concept of risk with respect to cytomegalovirusinfection in the current era of immunosuppression.

Natural History of Cytomegalovirus DiseaseAfter Solid Organ Transplantation

Although the virus remains latent in themajority of the population, cytomegalovirus mayreactivate during periods of inflammation,cytokine release, immunosuppression, orallogeneic stimulation.3 In solid organ transplantrecipients, cytomegalovirus infection may occuras primary infection in the seronaïve recipient oras reinfection in the seropositive recipient, as thetransplanted organ or blood transfusions canserve as vehicles for viral transmission. It isestimated that the risk of cytomegalovirustransmission associated with transfusing one unitof blood is 1–3% in the United States, even withthe use of filtered, leukocyte-poor packed redblood cells.8

In the absence of antiviral preventive therapy,cytomegalovirus infection, usually developingwithin 3 months of transplantation, presents as aspectrum of illnesses ranging from asymptomaticinfection to specific target organ involvement tosevere life-threatening disease. Without preventionstrategies, early-onset cytomegalovirus infectionmay occur in 60–80% and cytomegalovirusdisease in 20–40% of kidney transplant recipients,depending on cumulative risk factors.3, 9, 10 Theincidence of cytomegalovirus disease amongrecipients of extrarenal organs varies, withintestine, liver, and lung recipients at highest risk.11

Direct Effects of Cytomegalovirus

To separate the effects of invasive viral infectionfrom the consequences of the host inflammatoryresponses, the clinical manifestations of cyto-megalovirus replication in transplant recipientsare categorized as either direct or indirect.3

Direct cytopathic effects of the virus most oftenresult in the familiar cytomegalovirus syndrome,with fever, neutropenia, and thrombocytopeniaaccompanied by positive results of cytomegalo-virus polymerase chain reaction (PCR) testing.1, 3, 6

Tissue-invasive disease usually includes the viralsyndrome, but the presence of cytomegalovirusin various organs is confirmed by tissue biopsy.Other manifestations of cytomegalovirus includecompartmentalized disease such as gastrointestinalcytomegalovirus disease and cytomegalovirusretinitis (rarely seen in transplant recipients butoccurring at higher frequency in patients infectedwith the human immunodeficiency virus).12

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From the Department of General Surgery, Section ofTransplantation, Wake Forest University Baptist MedicalCenter, Winston-Salem, North Carolina (Dr. Stratta); andCTI Clinical Trial and Consulting Services, Cincinnati, Ohio(Drs. Pietrangeli and Baillie).

Manuscript preparation supported by CSL Behring, Kingof Prussia, Pennsylvannia; the authors are responsible for allcontent.

For reprints, visit http://www.atypon-link.com/PPI/loi/phco.For questions or comments, contact Robert J. Stratta, M.D.,FACS, Department of General Surgery, Wake ForestUniversity Baptist Medical Center, Medical Center Boulevard,Winston-Salem, NC 27157; e-mail: [email protected].

PHARMACOTHERAPY Volume 30, Number 2, 2010

Indirect Effects of Cytomegalovirus

In addition to the direct effects of viral infection,cytomegalovirus infection has been associatedwith acute and chronic rejection and decreasedgraft survival.3, 13–19 The indirect effects of cyto-megalovirus infection are related to the release ofimmunomodulatory mediators, contributing toan increased net state of immunosuppression, agreater risk of other opportunistic infections orsuperinfections, and dysregulation of cellularproliferation contributing to oncogenesis. Theseeffects of cytomegalovirus infection are believedto be caused by virally induced disruption ofantigen and cytokine expression and endothelialcell damage, resulting in an increased risk ofallograft injury manifesting particularly aschronic allograft damage.

Consequences of Cytomegalovirus Infection andDisease

Cytomegalovirus infection and disease havebeen associated with high mortality, as well asacute and chronic allograft injury. One groupdescribed a relative risk (RR) of long-termmortality of 2.79 (95% confidence interval [CI]1.55–5.01, p<0.001) in kidney transplantrecipients with asymptomatic cytomegalovirusinfection, and 2.48 (95% CI 1.30–4.74, p=0.006)in recipients who developed cytomegalovirusdisease.10 In the same study population, thisgroup of authors reported that asymptomaticcytomegalovirus infection (RR 2.90, 95% CI1.61–5.22, p=0.001) and overt cytomegalovirusdisease (RR 2.50, 95% CI 1.31–4.79, p=0.006)during the first 100 days after transplantationincreased the risk of recipient mortality beyond100 days.18–20

Such studies suggest that the long-term impactof cytomegalovirus infection and disease goes wellbeyond the traditional manifestation of the directeffects of cytomegalovirus infection observed inthe first few months after transplantation.Although more investigation into the role of theindirect effects of cytomegalovirus infection onlonger term patient and graft survival outcomes isnecessary, recent trials have suggested a benefit ofprophylaxis for cytomegalovirus infection on theseoutcomes.18, 21, 22

Timing of Cytomegalovirus Infection and Disease

As mentioned earlier, cytomegalovirus infectionusually occurs within the first 3 months aftertransplantation in the absence of antiviral prophy-

laxis when the degree of pharmacologic immuno-suppression is most intense and the risk ofallogeneic stimulation and acute rejection arehighest.7 Delayed-onset cytomegalovirus infectiondenotes the occurrence of infection in the first1–3 months after cessation of antiviral prophy-laxis.23, 24 It is important to understand that mostcytomegalovirus prevention strategies havemodified the epidemiology of posttransplantationcytomegalovirus infection from early- to delayed-onset cytomegalovirus infection. Late-onsetcytomegalovirus infection, which refers to casesoccurring more than 1 year after transplantation,may have atypical clinical features and a distinctpathogenesis, and may not be associated withconventional risk factors for early- or delayed-onset cytomegalovirus infection.25–29

The use of antiviral prevention strategies hascontributed substantially to a decrease in cytomega-lovirus-associated morbidity and mortality in theearly posttransplantation period.30–33 Nevertheless,even with modern regimens of prophylaxis, up to30% of high-risk patients develop delayed- orlate-onset cytomegalovirus infection after transplan-tation.31, 33, 34 Consequently, patients identified athigh risk for cytomegalovirus infection routinelyreceive antiviral agents and, in some settings,cytomegalovirus hyperimmune globulin forprophylaxis.

Several transplantation-related societies andprofessional organizations worldwide havepublished guidelines for the prevention ofcytomegalovirus infection after solid organtransplantation.35–37 These guidelines incorporatepublished evidence from large multicenterclinical trials, meta-analyses, individual trans-plantation center experiences, and expert opinion.Despite these contributions, there is no single testto accurately define the risk of cytomegalovirusinfection for a given transplant recipient. Inmany cases, the clinical trials and experiencesthat form the basis of the guidelines do not reflectcurrent patient populations, immunosuppressiveregimens, or clinical practice. Furthermore,differences in study methodology and variabilityin definitions may obscure the true incidence andprevalence of cytomegalovirus infection anddisease, and dissimilar study end points preventdirect comparison of results. For example, manyearly studies of prophylaxis for cytomegalovirusinfection were performed before widespreadavailability of diagnostic techniques based onPCR or antigenemia.

In the absence of a universally accepted,evidence-based best practice for prevention of

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cytomegalovirus infection after solid organtransplantation, prophylaxis strategies are guidedby knowledge and identification of risk factorsfor developing cytomegalovirus infection in theposttransplantation setting.

Assessment of Risk

The frequency of cytomegalovirus infection aftertransplantation is the end result of the interactionbetween factors that either favor or inhibit viralreplication or reactivation.7 Therefore, riskassessment for the development of cytomegalovirusinfection and disease is a product of evaluatingpatient and donor characteristics and choosingappropriate assays to measure viral activity.Several review and guidelines articles documentthe recipient-donor risk factors for the develop-ment of cytomegalovirus infection and disease(Table 1).1, 7, 35, 36 One investigator has simplifiedthis scheme into three major categories6: recipientserostatus, viral load, and immunosuppressiveregimen. In turn, the immunosuppressive loaddirectly affects the recipient’s ability to retain anddevelop anti-cytomegalovirus immunity aftertransplantation.

Donor and Recipient Serostatus

Serostatus of the donor and recipient is the keydeterminant in assessing the degree of cyto-megalovirus infection risk. Cytomegalovirus-seronegative recipients of organs from cyto-megalovirus-seropositive donors (primarycytomegalovirus exposure) are at highest risk for

developing cytomegalovirus infection in theposttransplantation setting.

Before the era of cytomegalovirus prophylaxis,50–60% of seronegative recipients of seropositive-donor organs experienced direct infectiousdisease manifestations from primary cytomegalo-virus exposure 4–12 weeks after transplantation.3

These findings apply to seromismatched kidneytransplant recipients; the incidence of diseasewill vary according to transplant type and the netburden of immunosuppression. Of note, pediatrictransplant recipients are more frequentlyseronegative recipients of organs from seropositiveadult donors. Although 50–80% of adults in theUnited States are seropositive for cytomegalo-virus, less than 50% of patients with type 1diabetes mellitus who are awaiting a kidney orpancreas transplant are cytomegalovirusseropositive, which places them at higher risk forprimary cytomegalovirus infection in the absenceof cytomegalovirus-seronegative matching.40, 41

Transplant recipients with primary cytomegalo-virus exposure are at the highest risk for cyto-megalovirus infection and the development oftissue-invasive cytomegalovirus disease, prophy-laxis failure (development of cytomegalo-virusinfection during the period of prophylaxis),cytomegalovirus relapse or recurrence, delayed-and late-onset cytomegalovirus infection,high–viral-load cytomegalovirus infection,ganciclovir-resistant cytomegalovirus strains, andindirect manifestations of cytomegalovirusinfection.35 Patients with primary cytomegalovirusexposure may benefit from combination strategies

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Table 1. Conventional Risk Factors for the Development of Cytomegalovirus Infection and/or Disease1, 6, 13, 38, 39

Risk Factor ExamplesSerologic status All transplanted organs: donor seropositive and recipient seronegative

Donor or recipient seropositive

Immunologic factors Recipient-donor human leukocyte antigen mismatchAllograft rejection

Level of immunosuppression Lymphocyte-depleting antibody therapy (antithymocyte-antilymphocyte globulin,lemtuzumab, OKT3)

Nondepleting antibody therapy (basiliximab, daclizumab)Calcineurin inhibitors (tacrolimus, cyclosporine)Antimetabolites (mycophenolate acid derivatives, azathioprine)Mammalian target of rapamycin inhibitors (sirolimus, everolimus)

Recipient and donor factors Type of transplanted organ: intestine, liver, lung associated with highest riskDeceased donor associated with greater riskExtremes of recipient ageRetransplantationBlood transfusion(s), plasmapheresisHypogammaglobulinemia

Viral factors High viral loadConcomitant viral infection: human herpesvirus-6, human herpesvirus-7, sepsis


that include the use of cytomegalovirus hyper-immune globulin.42–45

The seronegative recipient of a seropositive-donor organ usually undergoes seroconversionassociated with either a subclinical or clinicalcytomegalovirus infection during the first yearafter transplantation. However, approximately25% of recipients do not undergo seroconversion.In patients who do not seroconvert afterdocumentation of cytomegalovirus infection ordisease, the risk for cytomegalovirus infection ordisease relapse or recurrence remains high.46 In alung transplant recipient at risk for primarycytomegalovirus infection who receivedprolonged ganciclovir prophylaxis for 5.5 yearsand never seroconverted, cytomegalovirusinfection subsequently developed 6 weeks aftertermination of prophylaxis.47 It has beensuggested that these patients may benefit fromprolonged prophylaxis.

Cytomegalovirus seropositivity in either thedonor or recipient places a transplant recipient atintermediate risk for cytomegalovirus infection.36

In addition, superinfection with a donor strain aswell as reactivation of recipient latent virus canoccur in the seropositive recipient of a sero-positive-donor organ. In the kidney-pancreassetting, approximately 25% of this populationmay develop cytomegalovirus infection.48 In theseropositive recipient of a seronegative-donororgan, approximately 10–15% experience directinfectious disease syndromes as a result ofreactivation of latent virus in the host with theuse of conventional immunosuppression regimens.3

However, seropositive recipients of thoracictransplants are usually considered at the samehigh level of risk as seronegative recipients.49

Risk for cytomegalovirus infection is oftendismissed or considered to be low in the rela-tively uncommon situation of a cytomegalovirus-seronegative donor and seronegative recipient.However, the frequency of cytomegalovirusinfection in the seronegative donor–seronegativerecipient category is not trivial; it was approxi-mately 14% in one study of kidney transplantrecipients conducted in the United Kingdom.50

Certain seronegative recipients of a seronegative-donor organ develop overwhelming primaryinfection even years after transplantation. Thisatypical pattern of infection may be related totransmission of cytomegalovirus infectionthrough transfusion of blood products,manifestation of false-negative cytomegalovirusserology in the hemodiluted donor, or throughnatural transmission in the community.51, 52

One method of effectively reducing the risk forprimary cytomegalovirus infection is protectivematching, which is the practice of transplantingan organ from a cytomegalovirus-seronegativedonor to a seronegative recipient. Althoughprotective matching may not be logisticallyfeasible in most instances, it may be used inselected situations, including pediatric recipientsand cytomegalovirus-seronegative recipients ofintestinal and lung transplants. However, thispractice does not prevent natural transmission inthe community or transmission through bloodtransfusion.41 Methods to induce host immunityto cytomegalovirus through the use of vaccines,blood transfusions, or preparations to stimulateantibody production have not been reproduciblysuccessful.53–56

Viral Load

The degree of viral replication has been directlyassociated with the development of cytomegalo-virus disease.57 The single most important riskfactor for high viral load appears to be primarycytomegalovirus exposure. Other factors thatmay influence viral load include type oftransplant, method of prophylaxis, and overalllevel of immunosuppression.

Peak viral load is an important correlate of thedirect effects of cytomegalovirus infection. Onereview of the earlier literature suggested thatcytomegalovirus-DNA levels of greater than50–60 pg/ml of whole blood are predictive ofmore severe cytomegalovirus disease.58 In asubsequent study of liver, kidney, and bonemarrow recipients, the authors reported that boththe load of cytomegalovirus in the initial phase ofinfection and the rate of increase in viral loadcorrelated with the development of cytomegalo-virus disease.59 In a univariate analysis, each 0.1-log10 increase in viral load (expressed ascytomegalovirus genomes/ml/day) was associatedwith an odds ratio of 2.04 for the development ofcytomegalovirus disease (p<0.001).

High viral load or clinical circumstances thatfavor viral reactivation influence the naturalhistory of cytomegalovirus infection. The risk ofcytomegalovirus viremia or disease increasesexponentially with increases in viral load.57 Viralreplication is dynamic, with a doubling time ofapproximately 1 day.2 One study reported thatviral load at the initiation of therapy, virusdoubling time before therapy, and the half-life ofviral decline after initiation of therapy all affectedtreatment response.60 Although peak viral load

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has been established as a risk factor for the directand indirect effects of cytomegalovirus infection,persistent low-level viremia may be an additionalrisk factor for the indirect effects of cytomegalo-virus.13, 59, 61

Because cytomegalovirus appears to reside inmyeloid cells and some lymphoid cell popula-tions, a hierarchy of risk for cytomegalovirustransmission and subsequent viral infectionappears to exist according to type and number oforgans transplanted, and their relative content ofmyeloid cells.62 Transplantation of intestine,liver, and lung allografts may be associated with ahigher risk of cytomegalovirus transmission andhigher viral loads because these organs maycontain greater numbers of cytomegalovirus-infected myeloid cells.63–66 Similarly, multipleorgan transplants may carry a greater risk thansingle organ transplants for the same reason.Heart and pancreas allografts appear to carry anintermediate risk, whereas renal allografts mayhave a lower risk of cytomegalovirus transmissionbecause of viral load. Compared with solid organtransplants, blood transfusions appear to posethe lowest risk of cytomegalovirus transmission,but the number of blood products administeredmay have a cumulative effect on the risk ofcytomegalovirus transmission independent of theorgan transplanted.67–70

Anticytomegalovirus Immunity andImmunosuppression

Evidence from immunologic investigationsstrongly suggests a critical requirement for bothhelper and cytotoxic cytomegalovirus-specific Tcells to maintain anticytomegalovirus hostdefenses.71–73 It is generally recognized that thedetection of cytomegalovirus viremia is anindication of overimmunosuppression. Monitoringthe reconstitution of cytomegalovirus-specificCD4+ and CD8+ T-cell immune responses aftertransplantation has been proposed as a means ofevaluating the risk for cytomegalovirus infection,and to guide preventive therapy.74, 75

In the future, it is possible that risk assessmentfor cytomegalovirus infection may be based onconvenient and quantifiable assays of cytomegalo-virus-specific immune responsive-ness. Currently,the ImmuKnow assay (Cylex, Inc., Columbia,MD), measuring adenosine 5′-triphosphateproduction by CD4+ T lymphocytes, is approvedby the United States Food and DrugAdministration to monitor cell-mediated immunefunction in immunosuppressed patient popula-

tions.76 We have observed the utility of cyto-megalovirus viremia as an in vivo posttransplan-tation immune monitoring assay (unpublisheddata, R. Stratta, M.D., 2009).

Clearly, the role of a patient’s net level ofimmunosuppression as a risk factor for cyto-megalovirus infection and disease after transplan-tation cannot be discounted. The net level ofimmunosuppression in a given patient isdetermined by a number of nontransplant factorssuch as preexisting immunity and coexistingmedical conditions such as diabetes mellitus,uremia, cirrhosis, and malnutrition. Additionalfactors include the cause of organ failure, age andrace, existence of neutropenia or lymphopenia,and concurrent infection that may result in cytokinerelease or immunomodulation. In a transplantrecipient, the net level of immunosuppression isalso determined by the donor source, the degreeof human leukocyte antigen (HLA) mismatchand taboo HLAs, the presence and severity ofrejection, the intensity of prophylaxis, and thedose, duration, combination, and temporal sequenceof immunosuppressive drugs deployed.1, 77, 78

Both induction and maintenance immunosup-pressive drugs can alter cytomegalovirus-specific,cell-mediated, and humoral immune responsesthat lead to cytomegalovirus infection anddisease.7 The trend in clinical practice to sparethe use of maintenance agents such as cortico-steroids or calcineurin inhibitors has contributedto the increased use of more potent depletingantibody induction therapy with polyclonal andmonoclonal biologic agents. For example,between 1997 and 2006, the use of inductiontherapy during kidney transplantation increasedfrom 35% to nearly 80%, with the use ofThymoglobulin (antithymocyte globulin [rabbit];Genzyme Corp., Cambridge, MA) increasingfrom 5% to over 40%.79

Induction Therapy

Nondepleting monoclonal antibodies targetingCD25 (basiliximab and daclizumab) have notbeen consistently associated with an increasedrisk of cytomegalovirus infection or disease.80, 81

In contrast, in recipients of kidney-pancreastransplants, the use of polyclonal lymphocyte-depleting antibody agents such as rabbitantithymocyte globulin has been linked to ahigher risk of cytomegalovirus infection.82–84 Themechanism may be related to fever and therelease of tumor necrosis factor-�, stimulatingcellular nuclear factor–� B binding to the

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promoter region of the cytomegalovirus immediate-early antigen gene.85, 86 The depletion of helper Tcells, inversion of the CD4:CD8 ratio, and a shifttoward TH2 cytokines have also been proposedas events favoring cytomegalovirus replication inpatients treated with antithymocyte globulin.87, 88

Compared with basiliximab, use of thehumanized monoclonal anti-CD52 monoclonallymphocyte-depleting agent alemtuzumab hasbeen associated with a significantly higher rate ofcytomegalovirus infection in recipients ofsimultaneous kidney-pancreas transplants(29.3% vs 16.4%, p=0.002).81 Of interest, in thisstudy, analysis of donor-recipient serologyrevealed that a statistically higher rate ofcytomegalovirus infection was achieved only inseropositive donor–seropositive recipient trans-plant pairs. In the setting of early corticosteroidwithdrawal, alemtuzumab may not be associatedwith an increased risk of cytomegalovirusinfection.89, 90 Taken together, the evidencesuggests that the trend to use more potentinduction therapy may require a reexamination ofcurrent approaches to cytomegalovirus infectionprophylaxis.

Maintenance Immunosuppression

Regardless of the use of induction therapy,maintenance agents such as mammalian target ofrapamycin inhibitors may reduce the risk ofcytomegalovirus infection or disease. Oneanalysis of the Spanish transplant registryrevealed an odds ratio of developing cyto-megalovirus disease of 0.27 (95% CI 0.1–0.78)among kidney and kidney-pancreas recipientsreceiving sirolimus immunosuppression.91 Aseparate pooled analysis of clinical trials comparedthe use of sirolimus with calcineurin inhibitorsand antimetabolites.78 The investigators reportedan odds ratio for cytomegalovirus infection of0.64 associated with sirolimus use versus otherimmunosuppressive agents (p=0.047), 0.39versus antimetabolites (p=0.012), and 0.58versus the use of calcineurin inhibitors(p=0.054). However, calcineurin inhibitor–basedmaintenance immunosuppression is alsoassociated with lower rates of acute rejection,which may reduce the risk of cytomegalovirusinfection.

Cytomegalovirus and Acute Rejection

The interaction between cytomegalovirusinfection and acute rejection appears to bebidirectional.10, 92, 93 The presence of cytomegalo-

virus infection may result in a requisite reductionin immunosuppression and also cause immuno-activation with upregulation of major histocom-patibility complex class II antigen expression onallograft tissue, both of which could provoke anepisode of acute rejection. Conversely, the requisiteincrease in immunosuppression and use of anti–T-cell therapy to treat an acute rejection episodecould temporarily result in a reduction in immuno-surveillance and trigger activation of latentcytomegalovirus in monocytes through the releaseof cytokines, leading to active viral replication. Inpractice, acute rejection usually precedes cyto-megalovirus infection rather than vice-versa.94

Consequently, the presence of acute rejection,although it implies underimmunosuppression, isusually an indication to resume or continueanticytomegalovirus prophylaxis in concert withthe treatment of the rejection episode.

A hierarchy of risk for acute rejection mayoccur not only with different organ transplantsbut also when multiple organs are transplanted,either sequentially from different donors orsimultaneously from the same donor. A numberof theories have been offered to explain thisclinical observation, including variations inantigen presentation, antigen load, immunerecognition, and even partial tolerance.95 Unlikethe hierarchy of risk for potential cytomegalo-virus transmission associated with the trans-plantation of myeloid cell mass, because the liveris believed to be tolerogenic, the risk for acuterejection with a liver transplant or other organscotransplanted with the liver appears to be lowercompared with other solid organs.96 Otherwise,the hierarchy of risk for either cytomegalovirustransmission or acute rejection are roughlyparallel, with multivisceral, intestinal, and lungtransplants at the high end of the spectrum, heartand pancreas allografts intermediate, and kidneytransplants at lower risk.63

In the lung transplantation setting, inflammationassociated with acute rejection may furthercontribute to cytomegalovirus reactivationduring periods of augmented immunosuppres-sion.49, 97 In the absence of cytomegalovirusinfection prophylaxis, earlier studies reportedthat the use of OKT3 to treat rejection after liveror kidney transplantation was also associatedwith an increased occurrence of cytomegalovirusinfection.98, 99 Therefore, patients who receivelymphocyte-depleting antibody therapy either forinduction or to treat rejection should beconsidered at high risk for cytomegalovirusinfection.35

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Additional Risk Factors for CytomegalovirusInfection

Other risk factors for cytomegalovirus infectionmay include organ transplant from a deceasedrather than living donor, female recipient,development of delayed graft function, extremesof recipient age, retransplantation, need formultiple transfusions, coinfection with otherimmunomodulatory viruses (human herpesvirus[HHV]-6 or HHV-7), and insufficient antiviralprophylaxis.100 Compared with living-donortransplants, those from deceased donors areassociated with greater HLA mismatching, moredelayed graft function, a higher rate of acuterejection, and greater overall immunosuppressiveburden, all of which may contribute to a higherrisk of cytomegalovirus infection and disease.39,

101–105 Among kidney transplant recipients,delayed graft function is usually associated with ahigher initial immunosuppressive burden andmore acute rejection, both of which could resultin a greater risk for cytomegalovirus infection.Patients at the extremes of age may have less robustimmune systems, independent of cytomegalovirusseroreactivity, that could result in greater sensi-tivity to immunosuppression and vulnerability toopportunistic infections such as cytomegalovirus.

Retransplantation is typically associated withgreater cumulative or chronic immunosuppression,multiple operations and transfusions, enhancedalloimmunity, a higher risk of acute rejection,and the potential for repeated exposure tocytomegalovirus from a second allograft, all ofwhich could increase the risk for subsequentcytomegalovirus infection. Transfusion of bloodproducts poses a cumulative risk for cytomegalo-virus transmission, whereas coinfection withHHV-6 or HHV-7 may be surrogate markers forcytomegalovirus infection risk.39 The intensityand duration of antiviral prophylaxis play animportant role in determining the occurrence,timing, and severity of subsequent cytomegalo-virus infection or disease.105

More recently defined, novel risk factors forcytomegalovirus infection include thefollowing41–43, 46, 47, 51–56, 106:

• Toll-like receptor 2 and 4 polymorphisms• Mannose-binding lectin deficiency• Chemokine and cytokine defects (interleukin-

10, monocyte chemoattractant protein–1,chemokine (C-Cmotif) receptor–5)

• Lack of cytomegalovirus-specific CD4+ orCD8+ cells

• Coinfection with multiple cytomegalovirus

glycoprotein B (gB) genotypes

Related to the ability of the host to mountinnate and adaptive anticytomegalovirus immuneresponses, these emerging risk factors may proveclinically useful as assays are developed andresults are reliably correlated with clinical events.For example, absence of a CD8+ T-cell responseto cytomegalovirus, as measured by interferon-�release, may predict which patients are at greaterrisk for cytomegalovirus disease.

Assays of coinfection with multiple cyto-megalovirus gB genotypes, which may affect thecourse of disease, response to therapy, and occur-rence of acute rejection, provide one example. Ina study of 64 patients with solid organ andhematopoietic cell transplants, the authors foundthat in addition to an increased risk of progres-sion to cytomegalovirus disease, infection withmultiple gB genotypes resulted in a significantlyincreased frequency of allograft rejection comparedwith infection with a single gB genotype (93.3% vs61.8%, p<0.05).107

Working Definitions of High, Intermediate, andLower Risk for Cytomegalovirus Infection andDisease

The discussion of risk assessment provides abasis for working definitions of high, intermediate,and lower risk categories for cytomegalovirusinfection and disease according to donor-recipient serostatus, viral load, and recipientimmune status (Table 2).35, 36 The emergence ofone strong risk factor (e.g., extended use of a T-cell–depleting antibody preparation to treat acuterejection) in the presence of intermediate- orlower-level factors may in fact produce infectionand/or disease.

Prevention of Cytomegalovirus Infection andDisease

Other than refinements in immunosuppressiveregimens, some experts consider the control ofcytomegalovirus infection as the most significantadvance in organ transplantation in the past 20years.108 The primary goal of prevention ofcytomegalovirus infection is to improve long-term patient and graft survival. Preventionstrategies for cytomegalovirus infection in theposttransplantation setting are guided by theidentification of established risk factors and thetimeline for developing cytomegalovirus infection.

Standard prevention strategies include universalprophylaxis or preemptive therapy with antiviral

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agents with or without the addition of cytomegalo-virus hyperimmune globulin. Universal prophy-laxis is defined as the administration of a directedanticytomegalovirus therapy to all patients at riskfor cytomegalovirus infection for a specifiedperiod of time after transplant. In contrast,preemptive therapy is based on serial monitoringof a clinical or laboratory marker of cytomegalo-virus infection that serves as a trigger for theinitiation of specific antiviral therapy when itbecomes positive.38, 109

To our knowledge, there are no large randomizedcomparative trials of universal prophylaxis andpreemptive therapy in solid organ transplantpopulations. As a result, despite the publicationof guidelines to prevent cytomegalovirusinfection and disease, current approaches tocytomegalovirus prevention vary considerablyamong transplantation centers.35, 36

Nevertheless, the risk of cytomegalovirusinfection has been decreased with both universalprophylaxis and preemptive therapy regimens.110

Additional reported benefits of cytomegalovirusinfection prevention include improved long-termpatient survival, reduced severity of cytomegalo-virus disease, and fewer opportunistic andsecondary bacterial or fungal infections.33, 111–116

Cytomegalovirus prevention has also been associ-ated with reducing the costs of transplantation.117, 118

The universal prophylaxis approach providesantiviral therapy, such as valganciclovir orcytomegalovirus hyperimmune globulin, to all

members of a defined at-risk population. Theantiviral regimen is started immediately aftertransplantation and is continued for a definedminimum period of time, usually 100 days.110

The duration of prophylaxis may be extendeddepending on specific risk factors and the resultsof viral monitoring assays.

As an alternative, preemptive therapy usesserial monitoring for clinical or laboratorymarkers for the appearance of early cytomegalo-virus viremia as a trigger for the initiation ofantiviral therapy at therapeutic, not prophylactic,doses.109 The presence of viremia is indicative ofactive viral replication but is not sufficient todiagnose clinical (symptomatic) infection ordisease in the absence of other signs or symptoms.For this reason, viremia is often used as apreemptive marker of impending cytomegalo-virus “infection,” although in essence a distinc-tion is being made between subclinical andclinical or overt infection. Cytomegalovirus PCRor cytomegalovirus antigenemia assays form thebasis of the preemptive therapy strategy. Once apatient reaches a predetermined trigger level ofviral replication, preemptive anticytomegalo-virus therapy is started. Viral load reductionsmay be used to monitor response to antiviraltherapy, as well as to guide the duration ofantiviral therapy.57

Each of these prevention approaches isassociated with advantages and disadvantages.This has resulted in difficulty in defining the

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Table 2. Working Definitions of High, Intermediate, and Low Risk for Cytomegalovirus Infection and Disease After SolidOrgan Transplantation

Risk Factor High Risk Intermediate Risk Low RiskDonor-recipient serostatus Donor seropositive and recipient Donor or recipient Donor and recipient

seronegative seropositive seronegativePatients who fail to seroconvertSeropositive thoracic transplant recipients

Viral load58, 59 > 50–60-pg CMV-DNA/ml of whole blood Not described Not describedFor each 0.1-log10 increase in CMVgenomes/ml/day, odds ratio to developCMV disease 2.04 (p<0.001)

Concomitant viral infection with HHV-6,HHV-7, and/or sepsis

Recipient immunologic Induction with T-cell–depleting antibody Acute rejection Measureable anti-CMVstatus and immuno- preparations immunitysuppressive load Treatment of acute rejection with T-cell– Relatively low-level

depleting antibody preparations immunosuppressionor use of mammaliantarget of rapamycininhibitor

No acute rejectionCMV = cytomegalovirus; HHV = human herpesvirus.


optimal regimen for prevention of cytomegalo-virus infection after solid organ transplantationdespite several meta-analyses comparingoutcomes between these strategies.111–114

Although both strategies reduce the risk ofinvasive cytomegalovirus disease, prophylaxismay be associated with protection against someof the indirect effects of cytomegalovirus infec-tion, simpler logistics, and a decreased occur-rence of other herpesvirus and opportunisticinfections. The indirect immunomodulatoryeffects of cytomegalovirus infection, such aschronic allograft injury and acute rejection, alsoappear to be reduced in transplant recipients whoreceive prophylaxis for cytomegalovirusinfection.49, 119, 120

In general, universal prophylaxis has caused ashift from early- to delayed-onset cytomegalovirusinfection and disease.24, 121, 122 Delayed-onsetcytomegalovirus infection typically occurs at apoint in time when the patient is receiving lessoverall immunosuppression and is at lower riskfor acute rejection, both of which may contributeto less morbidity and fewer clinical manifes-tations associated with the infectious event.Preemptive therapy has not had this same effecton cytomegalovirus infection because preventionis not started until the detection of a specificmarker such as viremia. In contrast to universalprophylaxis, preemptive therapy has not beenassociated with late-onset cytomegalovirusdisease. In addition, preemptive therapy can beimplemented after a period of prophylaxis tofurther reduce the risk of either delayed- or late-onset cytomegalovirus infection.

Some experts believe that preemptive therapymay offer decreased exposure to antiviral drugs,potentially reducing the risk of viral resistanceand drug toxicity, as well as lowering drugcosts.109 However, successful use of preemptivetherapy requires significant resources forlogistical coordination.

Redefining Risk

Despite tremendous success in preventingdirect cytomegalovirus infection with availableagents, questions still remain as how to identifypatients at greatest risk and how to best optimizeprevention therapy for cytomegalovirus infectionand disease.

One author stated that although the currentstrategy of cytomegalovirus prophylaxis inkidney transplant recipients is imperfect, the easeof administration and the general overall

effectiveness of this approach is well accepted.108

An emerging concern is that some patientsdevelop cytomegalovirus infection or diseaseafter completing their prescribed antiviralprophylaxis regimen. The use of antiviralprophylaxis has shifted the onset of cytomegalo-virus infection from early to later after trans-plantation.24, 121, 122 Both delayed- and late-onsetcytomegalovirus infection have been recognizedto impact patient outcomes. In one study,delayed-onset cytomegalovirus infection wasdetermined to be strongly and independentlyassociated with overall mortality at 1 year in livertransplant recipients who received prophylaxis(hazard ratio 11, p=0.002).123 Cytomegalovirusdisease developed in 8.5% of recipients at amedian of 4.5 months after transplantationdespite prophylaxis, indicating that strategies toprevent delayed-onset cytomegalovirus infectionare warranted.

Primary cytomegalovirus exposure is the singlemost important risk factor for failure of primaryprevention, high–viral-load cytomegalovirusinfection, tissue-invasive cytomegalovirusdisease, cytomegalovirus relapse, ganciclovirresistance, delayed- and late-onset cytomegalo-virus infection, and the indirect manifestations ofcytomegalovirus infection.1 For these reasons,the duration of antiviral prophylaxis, ormonitoring in preemptive strategy regimens, hasbeen extended from 3–6 months to 6–12 monthsat some centers in patients at risk for primarycytomegalovirus infection or in those withmultiple risk factors.124

In the high-risk setting, both the AmericanSociety of Transplantation (AST) and CanadianSociety of Transplantation (CST) guidelines statethe preference of some centers to combine aganciclovir preparation with cytomegalovirushyperimmune globulin in kidney, liver, heart, andlung recipients (AST guidelines) or recipients ofthoracic transplants (CST guidelines).35, 36 LevelC evidence supports the combination, suggestingthat further, more stringent study is required.

Unfortunately, the available antiviral drugs areactive only against lytic, and not against latent,virus. Furthermore, toxicities associated with thecore anticytomegalovirus drugs ganciclovir andvalganciclovir may limit optimal therapy.125

Neutropenia, anemia, and thrombocytopenia, inparticular, are common hematologic toxicitiesassociated with cytomegalovirus-specific antiviraltherapies. In addition, these events may beexacerbated by the effects of induction andmaintenance immunosuppressive therapies and

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by the immunomodulatory effects of cytomegalo-virus infection.126

Some patients may develop cytomegalovirusinfections that are resistant to previously effectiveantiviral therapies.127, 128 Still others may developrecurrent cytomegalovirus infections or viralrelapse after therapy for cytomegalovirusinfection, which calls into question the need forand duration of secondary prophylaxis.129

Conclusion

Advances in both immunosuppression and thecontrol of cytomegalovirus infection and diseasehave contributed significantly to the improvedsuccess of solid organ transplantation. As newerinduction and maintenance agents and newcombinations of these agents are introduced intoclinical transplantation practice, we mustconsider their potential impact on the risk forcytomegalovirus infection. As many of theseinduction agents have not been studied in large,controlled, multicenter registration trials, theactual rate of cytomegalovirus infection is oftenunknown.

Although cytomegalovirus prevention strate-gies appear acceptable, special considerationsmay be needed in this modern era of immuno-suppression as we continue to understand theimpact of cytomegalovirus infection on long-termpatient and allograft outcomes. These specialconsiderations described above extend beyondthe traditional serostatus-based risk stratificationfor identification of patients at high risk forcytomegalovirus infection. In other words, thereare patients not recognized as high risk whoshould receive aggressive intervention forprevention of cytomegalovirus infection.

As our understanding of cytomegalovirusimproves, should we redefine risk for cytomegalo-virus infection by associating risk with specificcytomegalovirus-related outcomes? Instead ofgenerically identifying a patient as high risk forcytomegalovirus infection, should we be morespecific and classify patients as high risk fortissue-invasive cytomegalovirus disease, high riskfor late-onset cytomegalovirus infection, highrisk for resistant cytomegalovirus infection, orhigh risk for indirect effects of cytomegalovirusinfection, and design regimens of preventionaccordingly? This approach may allow us tobetter assess risk and associated outcomes on anindividual patient basis in order to implement amore appropriate preventive regimen.

Acknowledgments

The authors gratefully acknowledge Raymond R.Razonable, M.D., and Nina Singh, M.D., for theirexpert review of the manuscript.

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defining the risks for cytomegalovirus infection and disease after solid organ transplantation

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