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International Consensus Guidelines on theManagement of Cytomegalovirus in Solid

Organ TransplantationCamille N. Kotton,1,10 Deepali Kumar,2 Angela M. Caliendo,3 Anders Åsberg,4 Sunwen Chou,5

David R. Snydman,6 Upton Allen,7 and Atul Humar2; on behalf of The Transplantation SocietyInternational CMV Consensus Group9

Cytomegalovirus (CMV) remains one of the most common infections after solid organ transplantation, resulting in signif-icant morbidity, graft loss, and occasional mortality. Management of CMV varies considerably among transplant centers. Apanel of experts on CMV and solid organ transplant was convened by The Infectious Diseases Section of The TransplantationSociety to develop evidence and expert opinion-based consensus guidelines on CMV management including diagnostics,immunology, prevention, treatment, drug resistance, and pediatric issues.

Keywords: Cytomegalovirus, Prophylaxis, Resistance, Ganciclovir, Valganciclovir.

(Transplantation 2010;XX: 000–000)

S ignificant advances have been made in the managementof posttransplant cytomegalovirus (CMV); however, it

remains one of the most common complications affectingorgan transplant recipients, with significant morbidity andoccasional mortality. The adverse impact of CMV infectionon graft function underscores the importance of CMV ontransplant outcomes. Concurrent with recent advances in

molecular diagnostics, antiviral therapies, and evolving im-munosuppression regimens, management of CMV variesconsiderably among transplant centers. In December 2008, apanel of experts on CMV and solid organ transplant (SOT)was convened by The Infectious Diseases Section of TheTransplantation Society to develop consensus guidelines onCMV management. Topics include diagnostics, immunol-ogy, prevention, treatment, resistance, and pediatrics. Eachsection used a scoring system to rate the quality of evidenceon which recommendations are based (1) (Table 1). For clar-ity, the following definitions, which are consistent with theAmerican Society of Transplantation recommendations foruse in clinical trials (2), are used in this document.

• CMV infection: evidence of CMV replication regardlessof symptoms (differs from latent CMV).

• CMV disease: evidence of CMV infection with attribut-able symptoms. CMV disease can be further categorizedas a viral syndrome with fever, malaise, leukopenia, andthrombocytopenia or as a tissue-invasive disease.

DIAGNOSTICS

Pretransplant ManagementCMV serology should be performed pretransplant on

both the organ donor and the recipient. A test that measuresanti-CMV IgG should be used, because IgG serologic testshave better specificity than IgM tests or tests combining IgGand IgM, neither of which should be used for screening. False-positive IgM reactions may significantly decrease the specific-ity of the screen (3–5). Because donor and recipient serostatus(cited as D/R) are such key predictors of infection risk andmanagement, it is imperative that a test with high sensitivity

1 Transplant and Immunocompromised Host Infectious Diseases, InfectiousDiseases Division, Massachusetts General Hospital, Boston, MA.

2 Transplant Infectious Diseases, University of Alberta, 6-030 Katz-RexallCenter for Health Research, Edmonton, AB, Canada.

3 Department of Pathology and Laboratory Medicine, Emory UniversityHospital School of Medicine, Atlanta, GA.

4 Department of Pharmaceutical Biosciences, School of Pharmacy, Univer-sity of Oslo, Oslo, Norway.

5 Division of Infectious Diseases L457, Oregon Health & Science University,Portland, OR.

6 Division of Geographic Medicine and Infectious Diseases and Hospital Ep-idemiologist, Tufts Medical Center, Tufts University School of Medicine,Boston, MA.

7 Division of Infectious Diseases, Department of Pediatrics, Hospital for SickChildren, University of Toronto, Toronto, ON, Canada.

8 Transplant Infectious Diseases, Department of Medicine University of Al-berta, 6-030 Katz-Rexall Center for Health Research, Edmonton, AB,Canada.

9 The Transplantation Society International CMV Consensus Group (seeAppendix to this article).

10 Address correspondence to: Camille N. Kotton, Transplant and Immuno-compromised Host Infectious Diseases, Infectious Diseases Division,Massachusetts General Hospital, 55 Fruit Street, Cox 5, Boston, MA02114.

E-mail: [email protected] 6 October 2009. Revision requested 6 October 2009.Accepted 30 October 2009.Copyright © 2010 by Lippincott Williams & WilkinsISSN 0041-1337/10/XX0X-1DOI: 10.1097/TP.0b013e3181cee42f

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and specificity be used. Not all serologic tests are equivalent,and thus, it is important to understand the performance char-acteristics of the specific test used (6). A change in the sero-logic test requires an evaluation of the test performance,including comparison with the previously used test. If thedonor or recipient is seronegative during the pretransplantevaluation, serology should be repeated at the time of thetransplant if there is a significant time interval betweenscreening and the transplant. Interpretation of serology re-sults can be difficult in donors and recipients with recenttransfusion of blood products, as passive transfer of antibodycan lead to transient false-positive serologic results (7); a pre-transfusion sample is preferable if available.

In adults, an equivocal serologic assay result in thedonor should be assumed to be positive, whereas this resultin the recipient should be assumed to be negative. Thisstrategy will ensure that the recipient is assigned to thehighest appropriate CMV risk group for posttransplantmanagement decisions.

Posttransplant Role of DiagnosticsSerology has no role in the diagnosis of active CMV

disease posttransplantation. Viral culture of blood for CMVhas limited clinical utility for diagnosis of disease due to poorsensitivity. There is no role for CMV urine culture in thediagnosis of disease due to poor specificity (8). A positiveculture from bronchoalveolar lavage specimens in lung trans-plant recipients may reflect viral secretion and may not reflectpulmonary disease (9, 10). Culture of tissue specimens re-mains an option for diagnosis of tissue-invasive disease, par-ticularly for gastrointestinal samples, whereas antigenemia orpolymerase chain reaction (PCR) testing on blood may notalways be positive.

The CMV pp65 antigenemia test is a semiquantitativetest that is useful for the diagnosis of clinical disease, initiatingpreemptive therapy, and monitoring response to therapy(11–15). Studies have shown that higher numbers of positivestaining cells correlate better with disease (11, 12), althoughtissue-invasive disease can occur with low or negative cellcounts. Only one study showed a positive correlation betweenthe number of pp65-positive cells and CMV disease forD�/R� cases, because 82% of the D�/R� patients devel-oped CMV disease (16). The antigenemia test has advantages

in some settings, because it does not require expensive equip-ment and the assay is relatively easy to perform. There areproblems with a lack of assay standardization, including sub-jective result interpretation, and it is unlikely that better stan-dardization of this assay will occur, as more laboratoriesmove toward molecular methods. The assay may not be pos-sible to perform when the absolute neutrophil count is lessthan 1000 neutrophils/�L. The test is labor intensive, and theblood specimen has limited stability and should be processedwithin 6 to 8 hr of collection to avoid a decrease in test sensi-tivity. Transplant centers where many patients live far awayand whose blood samples are mailed to the laboratory mayprefer to use quantitative nucleic acid testing (QNAT) ratherthan antigenemia, given the decreased yield of antigenemiaover time.

QNAT for CMV (also known as CMV viral loadtesting) is the main alternate option for diagnosis, makingdecisions regarding preemptive therapy, and monitoring re-sponse to therapy (17–23). Most laboratories that performviral load testing are moving to real-time PCR technologies,because they have better precision, broader linear range,faster turnaround time, higher throughput, and less risk ofcarry over contamination compared with conventional PCRtests (24). The testing requires expensive equipment and re-agents, specialized expertise, and may not be appropriate forall laboratories. Plasma and whole-blood specimens bothprovide prognostic and diagnostic information regardingCMV disease (25–28). When using whole blood, the consen-sus opinion is to report values as copies per milliliter of blood,although there are no data directly comparing the impact ofreporting results based on volume of blood, micrograms ofDNA, or number of cells. CMV DNA is detected earlier andusually in greater quantitative amounts in whole blood com-pared with plasma. For this reason, one specimen type shouldbe used when serially monitoring patients.

The pp67 test (bioMerieux, Marcy l’Etoile, France) de-tects pp67 late mRNA in whole blood; there are limited dataon the clinical utility of this test (14, 17). As a qualitativeassay, it may be more appropriate for diagnosis of diseasethan for monitoring treatment response. Qualitative PCRis an option for surveillance if this is the only testing optionavailable, as there are problems with clinical specificity ofthis test and it is generally not recommended.

Currently, there is poor interinstitutional correlation ofQNAT viral load values, partly due to the lack of an interna-tional reference standard and variation in assay design (29).This prevents the establishment of broadly applicable cutoffsfor clinical decision making, particularly for preemptivestrategies. It is imperative that laboratories use an externalquantitative standard material (independent of that providedby the manufacturer) to monitor quantification across differ-ent lots of reagents to ensure consistency of assay perfor-mance. If the laboratory changes QNAT viral load tests orextraction method, there must be an evaluation of the perfor-mance characteristics of the new tests compared with the oldtests. Interinstitutional comparison of QNAT values requirescross-referencing of values by specimen exchange or use ofcommon external reference material (30).

Natural history studies have shown that higher viralload values correlate with increased risk for the developmentof disease (21, 22). One study (22) established a cutoff for

TABLE 1. Quality of evidence on whichrecommendations are based

Grade Definition

I Evidence from at least one properly randomized,controlled trial

II-1 Controlled trials without randomization

II-2 Cohort or case-control analytic studies

II-3 Multiple time series or dramatic uncontrolledexperiments (including data on new therapiesthat were not collected in a randomized fashion)

III Evidence from opinions of respected authoritiesbased on clinical experience, descriptive studies,or reports of expert committees

Adapted from CDC (1).

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predicting disease of 2000 to 5000 copies/mL in CMV-seropositive liver transplant recipients; this study was per-formed, however, using a commercial QNAT viral load test(Cobas Amplicor Monitor; Roche, Basel, Switzerland) and somay not be applicable in setting where other assays are used orin different populations and risk groups. Several recent pub-lications reporting equal efficacy of preemptive therapy touniversal prophylaxis in randomized trials in renal allograftrecipients used trigger points for intervention of more than2000 copies/mL of whole blood (9, 31, 32). Trends in viralloads over time may be more important in predicting diseasethan any absolute viral load value (21). The limit of detectionvaries among the different viral load tests; a lower limit ofdetection of greater than 1000 copies/mL (using either wholeblood or plasma) may be inadequate to detect disease (33)because some patients with end-organ disease may have verylow or even undetectable viral load values. Conversely, a sen-sitive test (limit of detection �10 copies/mL) may detect la-tent virus, particularly if whole blood specimens are used,which limits the clinical utility of an extremely sensitive test.QNAT viral load tests should be linear throughout the impor-tant range of clinical values (up to �1 million copies/mL).The precision of QNAT viral load tests are such that changesin values should be at least 3-fold (0.5 log10 copies/mL) torepresent biologically important changes in viral replication(34). QNAT variability is greatest for low viral loads; thus forviral load values at or near the limit of quantification, QNATviral load changes may need to be greater than 5-fold (0.7log10 copies/mL) to be considered significant.

Both the antigenemia and the QNAT viral load testshave clinical utility, are widely available, and in general thereis a good but not uniform correlation between CMV antigen-emia levels and QNAT viral load values (17, 24, 35). Onerecent study directly compared a whole-blood QNAT viralload test and the antigenemia test for use in initiating pre-emptive therapy (36) in SOT recipients and found that use ofthe viral load test for initiating preemptive therapy signifi-cantly reduced the number of patients requiring treatmentwith no increase in CMV disease. The decision regardingwhich test to use will depend on many factors including avail-able resources, technical expertise, patient population, re-quired turnaround time, volume of samples tested, and cost.Ideally, CMV QNAT and antigenemia tests should be avail-able within 24 to 48 hr for diagnosis of disease. For viral loadtesting, reporting results as both integers and log10 trans-formed data may help clinicians avoid overinterpreting smallchanges in viral load.

Diagnostics for Tissue-Invasive DiseaseSpecimens from specific body sites may provide addi-

tional information about CMV infection. Identification ofinclusion bodies or viral antigens in biopsy material by im-munohistochemistry (37, 38) or in bronchoalveolar lavagespecimens cells by immunocytochemistry may improve thepredictive value of a positive culture. The diagnosis of tissueinvasive CMV disease, such as hepatitis and gastrointestinal in-fection, should be confirmed by immunohistochemistry or insitu DNA hybridization (39–41). When performing histopa-thology of biopsy specimens, immunostaining should be rou-tinely performed to maximize sensitivity. Not all antibodies have

equal sensitivity, and the performance may also differ betweenfresh and formalin-fixed, paraffin-embedded tissue (41).

For bronchoalveolar lavage and biopsy specimens, lab-oratories should be moving toward QNAT testing because itprovides quantitative results, improved sensitivity withoutloss of specificity, and faster turn around time compared withculture (42, 43). The quantitative nature of QNAT may allowthe establishment of a viral load cutoff to predict the devel-opment of disease, without loss of specificity. At present,there are no randomized clinical data regarding the interpre-tation of QNAT viral load testing in bronchoalveolar lavagespecimens, although several studies suggest it may be helpfulin predicting pneumonitis (38, 43, 44).

Central nervous system disease in SOT recipients is ex-tremely rare. In the absence of extensive clinical studies, thepresence of CMV DNA in the cerebrospinal fluid (CSF) likelyrepresents CMV disease and should be treated. The diagnosisof retinitis is based on ophthalmologic examination; viralload in blood or plasma or other laboratory tests are rarelyuseful as predictors of CMV eye disease although they may bepositive before and at the time of diagnosis of CMV retinitis.

Future DirectionsNumerous questions remain unanswered in this field.

Future studies are needed to:

• Compare the performance characteristics of the differ-ent serologic tests; assess the utility of cell-mediated im-munity assays (45) for the interpretation of passiveimmunity due to transfusion of blood products and insorting out serostatus in donors and recipients less than18 months of age.

• Correlate viral load levels with immunohistopathology,in situ hybridization, and clinical outcome.

• Determine the characteristics of an international refer-ence standard that would optimize agreement betweenviral load values obtained with different tests.

• Determine the viral form (virions, fragmented, orgenomic CMV) in cellular and acellular compartmentsand viral kinetics in peripheral blood compartments.

• Directly compare QNAT viral load monitoring inplasma and whole blood with respect to disease predic-tion and monitoring response to therapy.

• Determine the role of antigenic variability among strainsand coinfection in predicting disease, relapse, and ther-apy response.

Consensus Recommendations

• Pretransplant donor and recipient serology should beperformed. If pretransplant serology of the recipient isnegative, retest at time of transplant (III). If the pretrans-plant serology is equivocal in the donor, assume it ispositive, and if the result is equivocal in the recipient,assume it is negative (III). (For guidance on infants andchildren less than 18 months, see Pediatrics section.)

• Viral culture of blood or urine has a limited role for thediagnosis of disease. Culture of tissue specimens hassome role in the diagnosis of invasive disease. Positiveculture of bronchoalveolar lavage samples may not al-ways correlate with disease (II-2).

© 2010 Lippincott Williams & Wilkins 3Kotton et al.

• Histopathologic examination of tissue should routinelyinclude immunostaining (II-2).

• Both antigenemia and QNAT viral load tests are accept-able options for diagnosis, decisions regarding preemp-tive therapy, and monitoring response to therapy (II-1/II-2). Transplant centers where many patients live faraway and whose blood samples are mailed to the labora-tory may prefer to use QNAT rather than antigenemia,given the decreased yield of antigenemia over time.

• Either plasma or whole blood is an acceptable specimenfor QNAT viral load testing, but there needs to be anappreciation of the differences in viral load values andviral kinetics in the two compartments. Specimen typeshould not be changed when monitoring patients (II-2).

• A universal cutoff for initiating therapy has not beenestablished due to issues outlined earlier. It is likely thatan international reference standard and consensus onspecimen type would improve the determination of ap-propriate standardized trigger points for intervention.In the interim, laboratories must establish their own cut-offs and audit clinical outcomes to verify the triggerpoints used (III).

IMMUNOLOGIC MONITORING FOR CMVAND CMV VACCINES

Immunologic Control of CMVThe immunologic control of CMV in the immuno-

compromised host is complex and involves both the innateand adaptive immune systems (46 – 48). Polymorphisms ofToll-like receptor-2 and Toll-like receptor-4 as well as defi-ciencies of complement proteins and mannose binding lectinare associated with increased risk of CMV disease (49 –51).Natural killer cells play a critical role in control of primaryand recurrent CMV infection, typically increasing in re-sponse to viral replication (52, 53).

Adaptive immune responses of B and T lymphocytesare critical in controlling CMV replication. The methods tomonitor the adaptive immune response to CMV may allowfor early identification of patients at increased risk of viralreplication. B cells are important in the humoral response toCMV, producing neutralizing antibodies that primarily tar-get glycoprotein B (gB) and glycoprotein H (46, 47). There isemerging evidence that a significant number of posttrans-plant patients develop hypogammaglobulinemia (26%–70%in some series), although a link with CMV risk is controver-sial. Hypogammaglobulinemia was a risk factor for CMV in-fection in heart and lung transplant recipients but not in alarge cohort of patients postliver transplant (54 –56).

T-cell responses, including both CD4� and CD8� Tcells, are critically important components of the immune sys-tem for control of CMV. Both CD4� T cells and CD8� cyto-toxic T lymphocytes protect against replication (46 – 48).T-cell reactivity has been shown to be directed toward a widerange of CMV antigens such as pp65, pp50, IE-1, gB, andothers (57). The key role of T cells in the control of CMV hasbeen demonstrated through the use of adoptive immuno-therapy for both prophylaxis and therapy of CMV infection,primarily in the hematopoeitic stem-cell transplantation(HSCT) setting. For immunotherapy, donor T cells arestimulated in vitro using viral lysate or CMV-specific pep-

tides and then transfused into the patient, resulting in con-trol of CMV replication in most cases (58). There are nodata available for the SOT population; this may be an ex-perimental strategy for CMV disease in those who are un-responsive to standard therapies.

Immune MonitoringImmune monitoring of CMV-specific T-cell responses

may predict individuals at increased risk of CMV diseaseposttransplant and be useful in guiding prophylaxis and pre-emptive therapies. There are a variety of T-cell assays forCMV. Most of these assays have been used in experimentalsettings, and widespread clinical application is still under in-vestigation. The majority of assays rely on the detection ofinterferon (IFN)-� after stimulation with CMV specific anti-gens (46 – 48). In addition to IFN-�, other markers, includinginterleukin (IL)-2, CD107, tumor necrosis factor-�, pro-grammed death (PD)-1, and CD154, can be used to correlatethe CMV-specific response with the risk of CMV. An idealassay should provide both CMV-specific CD4� and CD8�

T-cell quantitation (number of CMV-specific T cells) andfunction (number of CMV-specific cells that are functional).For ideal clinical application, an assay should be simple toperform, inexpensive, highly reproducible, and amenable toeither widely available platforms or shipping to specializedreference laboratories.

Each of the assays currently under investigation havespecific advantages and limitations and have been studied invarious clinical applications to predict disease or viremia(Table 2). The QuantiFERON-CMV assay (Cellestis Inc.,Melbourne, Australia) is currently the only commerciallyavailable kit and is an ELISA-based IFN-� release assay thatconsists of three tubes: negative control, mitogen or positivecontrol, and a tube with specific peptides targeting CMV spe-cific CD8� T cells. The assay has been evaluated in clinicalstudies and shown to have some predictive value for disease(59, 60) but not viremia. Interpretation of the test is unclear ifa posttransplant patient does not respond to the mitogencontrol. Nonresponse to mitogen may potentially be amarker for global immunosuppression, however, and war-rants further study. Test sensitivity decreases in lymphopenicpatients because an adequate number of cells are required forthe production of IFN-�.

The ELISPOT assay quantitates T-cells producingIFN-� in response to CMV. Purified peripheral blood mono-cyte cells (PBMCs) are stimulated with CMV-specific pep-tides or whole antigen lysates; IFN-� is then captured,detected, and quantified using a labeled antibody. As with theQuantiFERON assay, a mitogen control assays general T-cellresponsiveness. The ELISPOT assay cannot differentiateCD4� and CD8� T cells. Various in-house ELISPOT assayshave been evaluated and shown to be predictive of diseasebut not viremia (61). There is currently no standardizedELISPOT assay commercially available.

Most studies that have analyzed CMV-specific T-cellresponses have used intracellular cytokine staining (ICS) forIFN-� using flow cytometry. Whole blood or isolated PBMCsare stimulated with CMV peptides or CMV lysate. If wholeantigen lysate is used, the assay is not human leukocyte anti-gen (HLA)-restricted and knowledge of patient HLA type isnot required. Stimulated cells are stained with monoclonal



antibodies directed against IFN-�. This technique is fast, ver-satile, and can be expanded to include other cytokines and cellsurface molecules. Unlike the ELISPOT assay, ICS (andQuantiFERON) can provide both quantitative and qualita-tive characteristics of CMV-specific T cells. Clinical studieshave shown that this technique can predict both CMV diseaseand viremia. Several studies in SOT recipients showed an in-creased risk of CMV disease in patients with low levels ofspecific T-cell immunity (62– 64). Similarly, the absence ofanti-CMV T-cell response by this technique correlates withthe inability to clear viremia (62, 65, 66). Stable levels of CMVspecific CD4� T cells were associated with lower risk of CMVreplication (62, 66, 67). The development of T-cell immunityhas also been shown to be associated with freedom fromCMV disease after lung transplantation (68). The predictivevalue for viremia may be improved when the analysis ofIFN-� is combined with other cytokines such as IL-2 andadditional markers such as PD-1 (69, 70).

Major histocompatibility complex (MHC)-multimer-based assays directly stain peptide-specific T cells usingpeptide-conjugated MHC class I tetramers or pentamers.They can determine CD8� T-cell responses but are epitope-specific and require knowledge of the patient’s HLA type.Multimer assays combined with analysis of surface markerssuch as PD-1 have been shown to predict viremia and CMVdisease (69, 71). Both ICS and MHC-multimer staining re-quire a fluorescence-activated cell sorting facility, which maylimit widespread use in transplant centers.

The Cylex ImmunKnow assay (Cylex Inc., Columbia,MD) is not specific for CMV. This assay, which is commer-cially available in the United States and in some Europeancountries, measures overall immune response and serves as amarker of immunosuppression by determining the amountof ATP produced in response to whole-blood stimulation byphytohemagglutinin. A Cylex assay specific to CMV is availablefor research purposes and has been studied in a cohort of lung

TABLE 2. Advantages and limitations of various assays for immune monitoring of CMV

Assay Advantages Limitations CommentsPredictviremia

Predictdisease

Intracellular cytokinestaining

Whole-blood assay with low bloodvolume (1 mL) or PBMC

Needs access to a flowcytometer

Most data available withthis technique

Yes Yes

Short incubation time Not standardized Potential to freeze PBMCsand ship to referencelaboratory for testing

Results available within 24 hr

Knowledge of HLA not necessarilyrequired

Identification of CD4� and CD8�

T cells

Quantitative and qualitativecharacterization

QuantiFERON-CMV(Cellestis Inc.)

Whole-blood assay with low bloodvolume (3 mL)

CD8� responses only Approved in Europe Nodata Yes

Simple to perform Sensitive to lymphopenia

Results available after 30–40 hr Rare patients whose HLAtypes are not coveredin assay

Can be performed in any centerand stimulated plasma could besent to reference laboratory

ELISPOT Identifies both CD4�/CD8� T cells Need for purified PBMCfrom at least 10 mLblood

Potential to freeze PBMCsand ship to referencelaboratory for testing

No Yes

Knowledge of HLA not necessarilyrequired

Cannot differentiateCD4� and CD8� Tcells

Results available within 30–40 hr Not standardized

MHC multimerstaining

Fast assay (1–2 hr) CD8� responses only Unlikely to be used on awidespread basis

No No

Whole-blood assay with low bloodvolume (0.5–1 mL) or PBMC

Needs access to a flowcytometer

HLA and epitope specific

No information aboutfunction unlesscombined with ICS

Not standardized

Cylex ImmunKnow CD4� response Not specific for CMV Commercially available inUnited States

No No

PBMC, peripheral blood monocyte cell; HLA, human leukocyte antigen; CMV, cytomegalovirus; MHC, major histocompatibility complex.


transplant recipients to monitor CMV-specific responses over-time posttransplant (72). This assay has not yet been studied,however, to determine whether it is predictive of CMV viremiaor disease.

CMV VaccinesSeveral CMV vaccines are under development; none

are currently available for routine clinical use. Types of vac-cines includes live attenuated, DNA, subunit, and recombi-nant viral vaccines (48). A live attenuated vaccine based onthe Towne strain of CMV was found to be safe during clinicaltesting but had a suboptimal antibody response, and al-though CMV disease was attenuated, the vaccine failed toprevent infection (73, 74). Recombinant gB vaccine with ad-juvant has been shown to induce neutralizing antibodies (75)and prevent infection (76). Canarypox gB and pp65 vaccinesproduce T-cell responses and neutralizing antibodies (77,78). An alphavirus replicon vector system has been used toproduce viral particles expressing gB and pp65/IE-1 fusionprotein; initial studies in mice and rabbits have shown thedevelopment of neutralizing antibodies (79). An adenoviralchimeric vaccine-based replication deficient adenovirus en-coding gB and multiple CMV epitopes was able to produce arobust cellular response and neutralizing antibodies in mice(80). Currently, clinical trials in HSCT are underway with agB/pp65-based DNA vaccine (www.clinicaltrials.gov). A pre-vious study with this vaccine in both seropositive and sero-negative healthy volunteers showed promising results (81).Because CMV vaccines are in a preliminary phase, recom-mendations for the development and testing of vaccines weremade based on expert opinion.


• Hypogammaglobulinemia may play a role in CMV dis-ease posttransplant; the measurement of immunoglobu-lins may be considered posttransplant if CMV is difficultto control (II-2).

• Adoptive T-cell therapy has been used on an experimen-tal basis in HSCT recipients. No clinical studies for CMVin SOT exist. This is an area where further study isneeded (III).

• An ideal immune monitoring assay should provideCD4� and CD8� T-cell quantitation and function. Op-timally, the assay should measure IFN-�; additionalmarkers such as IL-2, PD-1, CD107, tumor necrosisfactor-� may have predictive value for viremia. Clinically,an ideal assay should be simple to do, rapid turnaroundtime, cost-effective, reproducible, and potentially ame-nable to allow shipping of specimens to a specializedreferral laboratory (III).

• Current evidence suggests that certain immunologicmonitoring tests can predict risk of CMV viremia anddisease in the postprophylaxis and preemptive setting(II-2/II-3). Few tests specific for CMV were commer-cially available at the time of this consensus meeting.

• At present, there are no clinical studies demonstratingthat management decisions based on immunologicmonitoring affect patient outcomes. Therefore, basedon current evidence, immunologic monitoring cannotbe recommended on a routine basis. Studies should be

conducted to understand the role of immune monitor-ing in making clinical decisions about the preventionand management of CMV viremia and disease (III).

• CMV vaccines are in preclinical and phase I trials. Theprimary goal of a CMV vaccine should be to preventCMV viremia or CMV disease and prevent secondaryendpoints such as rejection and graft loss (III). In theory,it is possible that vaccination may reduce burden of dis-ease or impact the course of latent CMV infection inseropositive patients, and vaccination trials should,therefore, focus both on seronegative and seropositiverecipients (III). Until further evidence is available, norecommendation can be made with regards to type ofvaccine or timing of vaccination.

PREVENTION OF CMVCMV prevention strategies have resulted in significant

reductions in CMV disease and CMV-related mortality. Theimprovements in the “indirect effects” of CMV infection havealso been attributed to the use of CMV prevention. Two ma-jor strategies are commonly used for prevention of CMV:universal prophylaxis and preemptive therapy. Within eachof these strategies, significant variation in clinical practice ex-ists, and hybrid models using both strategies are possible.

Universal ProphylaxisUniversal prophylaxis involves the administration of

antiviral medication to all patients or a subset of “at-risk”patients. Antivirals are usually begun in the immediate orvery early posttransplant period and continued for a finiteperiod of time, often in the range of 3 to 6 months. Severalantivirals have been evaluated for universal prophylaxis, in-cluding acyclovir, valacyclovir, intravenous (IV) ganciclovir,oral ganciclovir, and valganciclovir. In early studies, acyclovirwas determined to be inferior to ganciclovir for prevention ofCMV (82). A subsequent large study comparing oral ganci-clovir with valganciclovir in D�/R� transplant patientsdemonstrated equivalent efficacy of the two regimens, al-though concern was raised regarding an increased incidenceof tissue-invasive disease in the liver transplant patients whoreceived valganciclovir (83). Late onset CMV disease has beenthe most significant finding in all studies evaluating universalprophylaxis, defined as disease occurring after the discontin-uation of prophylaxis. In the PV16000 study, late-onset CMVdisease occurred in 18% at 12 months (and in closer to30% when including investigator treated disease) (83). Thedeterminants of late-onset CMV disease in patients receiv-ing prophylaxis have not been fully elucidated, but arelikely related to ongoing significant immunosuppression,accompanied by a lack of development of significant CMVspecific cell-mediated immunity. Risk factors for late-onset disease include D�/R� serostatus, higher levels ofimmunosuppression, and allograft rejection (84).

Preemptive TherapyIn preemptive therapy, laboratory monitoring is per-

formed at regular intervals to detect early, asymptomatic viralreplication. Once viral replication reaches a certain assaythreshold, and hopefully before the development of symp-toms, antiviral therapy is initiated to prevent the progression



to clinical disease. The advantages of preemptive therapy in-clude more selective drug targeting, decreased drug cost, andassociated toxicities. Theoretically, a preemptive strategy maypromote the development and maintenance of CMV-specificcell-mediated immunity by allowing low-level viral replica-tion. Preemptive therapy is more difficult to coordinate be-cause it requires weekly laboratory monitoring and a shortturnaround time in the laboratory. In addition, optimalthreshold values for antigenemia or viral load are assay de-pendent and have not been well established. In settings whereviral doubling time is rapid, there may be insufficient time todiagnose and begin treatment for CMV viremia before thedevelopment of symptoms. One of the major concerns withpreemptive therapy is that it may not prevent the indirecteffects of CMV infection, including effects on graft and pa-tient survival (85, 86). In addition, second episodes of repli-cation are observed in approximately 30% of patients treatedfor CMV disease, some of which require further therapeuticintervention (87). Patients who are D�/R�, certain trans-plant types (e.g., lung) and those on highly potent immuno-suppression are likely more prone to recurrent episodes ofviremia.

Universal Prophylaxis VersusPreemptive Therapy

A comparison of universal prophylaxis with preemp-tive therapy is provided in Table 3. There are only relativelysmall comparative trials of the two strategies. In one studycomparing oral ganciclovir prophylaxis to preemptive IVganciclovir in kidney transplant patients, prophylaxis re-duced CMV infection by 65% (13 vs. 33 patients), and graftsurvival was improved at 4 years posttransplant suggesting apossible beneficial effect of prophylaxis (85).

Consensus RecommendationsThe majority of consensus conference participants fa-

vored the use of prophylaxis over preemptive therapy in the

highest risk recipients (e.g., D�/R�), based on the availabledata suggesting better graft survival and clinical outcomes.Individual transplant centers should weigh the risks and ben-efits of each strategy, based on their frequency of CMV dis-ease, ability to monitor recipients (i.e., logistics), cost ofantiviral medications, frequency of late onset CMV disease,relapse failure rates with preemptive therapy, and rates ofother opportunistic infections (which may be increased byCMV disease), graft loss, rejection, and mortality. To mitigaterisk, some centers use a hybrid approach, especially for thoserecipients felt to be at high risk for late CMV disease, that is,preemptive therapy with treatment followed by secondaryprophylaxis or prophylaxis followed by preemptive therapy.

Use of Prophylaxis Versus Preemptive Therapy

• Both universal prophylaxis and preemptive strategiesare viable approaches for prevention of CMV disease (I).

• For the highest risk patients (D�/R�), prophylaxis mayhave some advantages over preemptive therapy (II/III).

• Preemptive therapy has not been well studied in somesubpopulations including lung transplant, intestinaltransplant, and pediatric transplant.

Prophylaxis StrategyWhen a prophylaxis strategy is used for prevention in

D�/R� patients, the following durations are recommended:

• The duration of prophylaxis in D�/R� patients should begenerally between 3 months (I) and 6 months (I). The de-cision to use 3 vs. 6 months may depend on degree of im-munosuppression, including the using of antilymphocyteantibodies for induction. The Improved Protection AgainstCytomegalovirus in Transplantation (IMPACT) studycompared 100 vs. 200 days of prophylaxis in 316 D�/R�kidney patients. The incidence of CMV disease was re-duced from 36.8% to 16.1% (88).

• A minimum of 6 months of prophylaxis is recom-mended for lung (II-2) and small intestine (III) trans-plant recipients.

When a prophylaxis strategy is used for prevention inD�/R� patients, the following antiviral medications arerecommended:

• Kidney transplant: valganciclovir, IV or oral ganciclovir,or valacyclovir (I).

• Pancreas transplant (including kidney/pancreas): val-ganciclovir and IV or oral ganciclovir (II).

• Liver transplant: oral ganciclovir (I) or valganciclovir(III). In a subgroup analysis, valganciclovir was associ-ated with a higher rate of tissue-invasive disease in livertransplant recipients (83), but its use is still recom-mended based on expert opinion; in one survey, it wasthe most commonly used drug for CMV prevention inliver transplant recipients (89).

• Heart transplant: valganciclovir, IV or oral ganciclovir(II), �CMV immunoglobulin (III).

• Lung transplant: valganciclovir or IV ganciclovir (II),�CMV immunoglobulin (III).

• Intestinal transplant: valganciclovir, IV or oral ganciclo-vir, �CMV immunoglobulin (III).

TABLE 3. Comparison of known benefits andlimitations of prophylaxis versus preemptive therapy

Effect Prophylaxis Preemptive

CMV disease ��

Late CMV disease ��

CMV relapse/treatment failure ��

Fewer opportunistic infections ��

Improved graft survival ��

Prevention of rejection ��

Survival ��

Other viruses � �

Posttransplant lymphoma � �

Kaposi sarcoma � �

Safety ��

Easier logistics ��

Lower drug cost � ��

Lower monitoring cost ��

Resistant CMV ��

CMV, cytomegalovirus; �, ease of use and strength of the evidence; ��,strongest evidence or favors the approach listed; �, no evidence exists.


When used for prophylaxis, the usual dose of valganci-clovir is 900 mg a day, versus treatment dose which is 900 mgtwice daily; both should be adjusted for renal function. Thereare limited data to support the use of CMV immunoglob-ulin for prophylaxis when appropriate antivirals are given.However, some centers use these products in conjunctionwith antiviral therapy, especially for thoracic transplantrecipients (III).

Important Considerations for Prophylaxis forD�/R� Patients

Dosing of antiviral medication should be based onstandard recommended dosing algorithms and adjusted forrenal function. “Mini-dosing” strategies (i.e., valganciclovir450 mg a day with normal renal function) are not recom-mended. Most centers do not test for CMV viremia in asymp-tomatic patients on antiviral prophylaxis. The occurrence oflate-onset disease after discontinuing prophylaxis is an im-portant issue and is associated with higher rates of mortality(90) and graft loss (91). Transplant centers should monitorclinically for signs and symptoms of late-onset CMV disease;additional strategies to prevent late onset disease may be con-sidered, including PCR or antigenemia monitoring aftercompletion of prophylaxis, or prolonging prophylaxis from 3up to 6 months or longer in certain subgroups of patients.

Prophylaxis of R�

• When a prophylaxis strategy is used for prevention inR� patients (with either D� or D�), a majority of theexperts felt that 3 months of antiviral medication shouldbe used for kidney, pancreas, liver, and heart transplantrecipients (I/II).

• In those receiving antilymphocyte antibody induction,or lung and intestinal transplant recipients, between 3and 6 months of prophylaxis can be used (III). The samemedications are recommended for this cohort as forD�R�.

• While D�R� patients are discussed here together withthe D�/R� group, the former group is usually at higherrisk for developing CMV disease.

Prophylaxis of D�R�In general, this population is at low risk for CMV dis-

ease. Extensive transfusion of blood products increases therisk of CMV disease (especially if not CMV screened or leu-kodepleted), and transplant centers may wish to monitorsuch recipients with weekly CMV PCR or antigenemia. Theuse of leukodepleted blood products and CMV-seronegativeblood products is recommended for these recipients to de-crease the risk of transfusion transmitted CMV (II). Sometransplant centers may give CMV antiviral prophylaxis in pa-tients who receive extensive transfusions (III).

• Antiviral prophylaxis against other herpes infections(varicella and herpes simplex) should be considered.

Preemptive Therapy Strategy

• When a preemptive therapy strategy is used, it is recom-mended that the center develop and validate their localprotocol. Because preemptive therapy relies on labora-

tory monitoring, it is important that an appropriatethreshold value be chosen for the specific assay that isused. There is currently insufficient evidence to recom-mend universal threshold values for assays that are usedin preemptive therapy. For optimal preemptive therapy,there was strong consensus that kidney, pancreas, liver,and heart transplants should be monitored by eitherCMV PCR or antigenemia every week for 3 months aftertransplant.

• Once a certain positive threshold (variable by assayused) is reached, therapy with treatment dose (not pro-phylactic dose) valganciclovir (I) or IV ganciclovir (I)should be started and continued until one or two nega-tive tests are obtained. Testing while on treatment is of-ten performed once or twice a week.

• Whether to reinitiate subsequent monitoring or second-ary antiviral prophylaxis after the end of treatmentshould be an institutional decision. Occasional low-levelunsustained viremia (i.e., below the institutional thresh-old for preemptive treatment) may be seen and shouldnot result in the initiation of antiviral treatment unlessthe patient is symptomatic; such low viremia may re-spond to a reduction in immunosuppression.

Prevention During Treatment of Rejection

• There was consensus that treatment of rejection withantilymphocyte antibodies in at-risk recipients shouldresult in reinitiation of prophylaxis or preemptive ther-apy for 1 to 3 months (II/III); a similar strategy may beconsidered during treatment of rejection with high-dosesteroids (III).

CMV TREATMENTIV ganciclovir has been the “gold standard” for treat-

ment of CMV disease for some years. Previously, foscarnetwas commonly used but toxicity generally limits use in SOTrecipients, especially the nephrotoxic effect in those receivingconcomitant calcineurin inhibitors (92). The Valcyte inCMV-disease Treatment of solid Organ Recipients (VICTOR)trial recently showed that oral valganciclovir is noninferior toIV ganciclovir for treatment of CMV disease in a populationof SOT recipients (74% of whom were renal transplant recip-ients) with generally nonlife-threatening disease as deter-mined by the investigator (48% had CMV syndrome and 49%had tissue-invasive CMV disease) (33). In patients with life-threatening CMV disease and in children, IV ganciclovir isstill the preferred drug, because data on the effect of oraltreatment are limited. IV ganciclovir should also be used inpatients who do not tolerate oral treatment or when absorp-tion of valganciclovir is suboptimal.

It is important to give appropriate doses of valganciclo-vir or ganciclovir. Inadequate dosing may result in lack ofclinical efficacy and promote resistance (93). Supratherapeu-tic doses may result in toxicity (94). Twice daily dosing shouldbe used for treatment of disease in patients with normal renalfunction. Once daily dosing is appropriate for secondary pro-phylaxis (see later). Optimal length of treatment should beachieved by monitoring weekly viral loads and treating untilone or two consecutive negative samples are obtained, butnot shorter than 2 weeks. With this treatment algorithm, the



risk for development of resistance and recurrence of CMVdisease is minimized (87, 95, 96). The use of secondary pro-phylaxis is variable across transplant centers, but it is oftenrecommended (range 1–3 months) (87, 33). Duration shouldreflect the likelihood of recurrent CMV infection. In cases ofserious disease and in tissue-invasive disease without viremia,longer treatment periods with clinical monitoring of the spe-cific disease manifestation are recommended. In cases of re-current CMV disease, prophylaxis after retreatment mayneed to be prolonged.

Clinical trials over the years have established severalrisk factors for recurrence of CMV include: primary CMVinfection (e.g., CMV IgG seronegative at start of treatment ofCMV disease), deceased donor transplantation, high baselineviral load, persistent viremia when transferred to secondaryprophylaxis, multiorgan disease, and treatment of rejection(87, 96 –98). Knowledge of these risk factors allows for someindividualization of the treatment, but only as a supplementto clinical and virologic monitoring of the patient.


• For nonsevere CMV disease, oral valganciclovir (900 mgorally every 12 hr) or IV ganciclovir (5 mg/kg every 12hr) are recommended as first-line treatment (I, [33]). Inchildren, in patients with severe or life-threatening dis-ease, and when the oral formulation of the drug is nottolerated or its absorption may be suboptimal, IV gan-ciclovir should be used, because there are no efficacydata for oral treatment in these cases (III). Conversionbetween the two drugs (i.e., from IV ganciclovir to oralvalganciclovir) may be performed without dosing inter-ruption (III). Oral ganciclovir, acyclovir, or valacyclovirshould not be used for treatment of CMV disease (III).Renal function should be monitored frequently duringtreatment, with estimated or measured glomerular fil-tration rate. The doses should be adjusted as per thepackage label (noting that there are different cutoffs forIV ganciclovir and oral valganciclovir) (II-1, [99]). Dosereduction of antiviral treatment due to side effects suchas leukopenia should be avoided as much as possible. Areduction of mycophenolic acid products, mammalian tar-get of rapamycin inhibitors, azathioprine, and possibly alsotrimethoprim-sulfamethoxazole dosages should be con-sidered before valganciclovir/ganciclovir reduction (III).Granulocyte colony-stimulating factor (G-CSF) may beconsidered for severe leukopenia, especially if the absoluteneutrophil count is less than 1000/mm3 (III). Redosing ofG-CSF depends on individual response to therapy.

• Treatment with twice daily valganciclovir or IV ganci-clovir should be continued until viral eradication isachieved, but not shorter than 2 weeks (II-1, [23, 87,33]). Risk factors indicating a possible need for longertreatment length are CMV IgG seronegativity and highbaseline viral load at the start of treatment (II-1, [33]).Secondary prophylaxis with 900 mg valganciclovir oncedaily for 1 to 3 months may be given, with the longerduration deployed in high-risk patients (II-3, [33]); doseadjustment based on estimated or measured renal func-tion should be made per the package insert.

• Laboratory monitoring of CMV should be appliedweekly during the treatment phase with a QNAT orantigenemia-based assay to monitor response and thepossible development of resistance (II-1, [23, 33]).Trends of serial monitoring are easier to interpret thanan individual test result. Two consecutive negative sam-ples (preferably sampled one week apart) ensure viralclearance (III). Periodic viral load monitoring shouldalso be performed during secondary prophylaxis (III);the correct time interval for monitoring is not known,but more frequent monitoring should be done inthose at high risk for breakthrough disease. Becausethe lower limits of detection of QNAT assays are vari-able, “undetectable” is an assay-specific term. Atpresent, when using extremely sensitive viral load as-says (which may detect latent virus), it is not knownwhether treatment to “undetectable” QNAT viral loadis required to minimize relapse risk.

• Dose reduction of the immunosuppressive therapyshould be individualized but should be considered insevere CMV disease, in nonresponding patients, inpatients with high viral loads, and with leukopenia(II-2, [100]). If the immunosuppressive therapy is re-duced, clinicians may wish to return to standard im-munosuppressive treatment when adequate clinicaland viral response is obtained (III). In case of recur-rent CMV disease, a general evaluation of the overallimmunosuppressive status of the patient should beperformed and immunosuppression adjusted whenindicated (III).

• The role of CMV immunoglobulin in the treatment ofCMV disease is unclear. It may be considered as adjunc-tive therapy for severe forms of CMV disease such aspneumonitis (III).

ANTIVIRAL DRUG RESISTANCE

Risk Factors for CMV Drug Resistance, ObservedFrequency, and Clinical Consequences

Published series identify the risk factors for drug resis-tance as prolonged antiviral drug exposure (usually severalmonths, median is 5 to 6 months) and ongoing active viralreplication as permitted by host immunosuppression or im-munodeficiency, lack of prior CMV immunity (D�R�), orinadequate antiviral drug delivery as with oral ganciclovir(evidence II-2) (92, 101–105). Among adult SOT recipients,ganciclovir resistance occurs overwhelmingly in the D�R�subset where the usual incidence of resistance is 5% to 10%(92, 102) and seems to be higher in lung transplant recipients(103, 106). There are no large studies comparing the out-comes of infection with drug-resistant versus drug-sensitiveCMV strains. Reported outcomes of drug-resistant CMV in-fection range from asymptomatic to severe or fatal disease(92, 102, 107, 108). Tissue-invasive CMV disease is frequentlyencountered in those who are infected with drug-resistantvirus. Virulent disease is common despite potential loss ofviral fitness due to the resistance mutation(s) present (93).

Diagnosis of Drug ResistanceAntiviral drug resistance is suspected when increasing

or high-level CMV viremia or progressive clinical disease is


observed during prolonged antiviral therapy. The in-creases in viral loads, especially in the first weeks of treat-ment, are not reliable indicators of drug resistance (109).Although the clinical risk factors for drug resistance arebecoming better defined, accurate diagnosis requires diag-nostic laboratory testing.

The traditional plaque reduction (phenotypic) sensi-tivity assay is used to determine the drug concentration re-quired to inhibit the growth of a viral isolate by 50% (IC50).This assay is impractical for routine patient care, because oftechnical complexity, difficulties with standardization, andslow turnaround time (at least several weeks). Phenotypicassays are required as reference standards for comparing thedrug sensitivity of viral strains, assessing the significance ofpreviously uncharacterized mutations, and setting cutoff cri-teria for diagnosing viral drug resistance.

Genotypic assays for rapid antiviral resistance testingare useful to identify characteristic viral mutations indicativeof drug resistance. Such assays are being performed by anincreasing number of commercial laboratories and can beperformed on viral sequences directly amplified from blood(whole blood, plasma, and PBMC), fluids (CSF and bron-choalveolar lavage), tissue specimens, or CMV culture iso-lates. The turnaround time for such assays varies dependingon the laboratory and geographical constraints. There are afew reports of discordant resistance mutations in differentbody compartments (110). This testing is more reliable if theCMV load in the specimen is at least 1000 copies/mL. Stan-dard sequencing technologies enable the detection of a mu-tant viral sequence when it increases to approximately 20% ofthe total sequence population (111). Amplification directlyfrom clinical specimens allows determination of the UL97kinase (codons 400 – 670) and (optionally) the UL54 pol(codons 300 –1000) sequences. A large and evolving databaseof characterized CMV drug resistance mutations has beenaccumulated (112–115). Existing data indicate that morethan 90% of ganciclovir-resistant CMV isolates contain UL97mutations at codons 460, 520, or 590 to 607. Mutations

M460V/I, C592G, A594V, L595S, and C603W are the mostcommon and confer a 5- to 10-fold increase in ganciclovirIC50, except for C592G that confers only approximately a2.5-fold increased IC50, considered low-grade resistance. Lesscommon sequence changes at codons 590 to 607 may confervarious degrees of ganciclovir resistance or no significant re-sistance. In the viral DNA polymerase gene (UL54, pol), drugresistance mutations tend to occur in the conserved func-tional domains and may confer resistance to any or all of thecurrent drugs ganciclovir, foscarnet, or cidofovir. Mutationsthat confer ganciclovir and cidofovir resistance are clusteredin the exonuclease domains and region V, whereas those con-ferring foscarnet resistance are often located in or betweenregions II, III, and VI. Some foscarnet resistance mutations inregion III confer a low-grade ganciclovir cross-resistance. Inpatients initially treated with ganciclovir, UL97 mutationsusually appear first, followed later by the addition of polmutations that confer increased ganciclovir resistance andcross-resistance to cidofovir or foscarnet (116 –118). Wheninterpreting genotypic assays, it is important to distinguishbaseline sequence polymorphisms of CMV strains (119, 120)from mutations that are proven to confer drug resistance(121, 122). The status of many observed sequence changes inUL97 and pol remain unresolved.

Selection of Alternate Therapy forDrug-Resistant CMV

No controlled trial data support a best practice for se-lection of alternate therapy when evidence of drug resistanceis present. An algorithm is proposed (Fig. 1) based on con-sensus opinion assembled for this publication (III). Clini-cally, antiviral drug resistance is suspected when high orrising viral loads and progressive CMV disease are observedafter substantial cumulative antiviral drug exposure and sev-eral weeks of antiviral therapy. This finding is sometimescalled “clinical resistance,” but many such cases reveal novirologic (genotypic or phenotypic) evidence of drug resis-tance, especially when the duration of drug exposure is less

FIGURE 1. Suggested algorithmfor management of suspected CMVdrug resistance. Treatment selec-tion is affected by host risk factors,immune competence, viral loads,disease severity, and dose-limitingtoxicities (see text). CMV, cytomeg-alovirus; GCV, ganciclovir; FOS,foscarnet; CDV, cidofovir.



than several months. Antiviral therapy may be insufficient tosuppress viral replication in the presence of adverse host fac-tors (e.g., immune impairment, inadequate drug levels), in-dependent of viral drug resistance. In this situation, the firstrecommended therapeutic change is to decrease immuno-suppressive therapy to the lowest feasible amount. Then, de-pending on the severity of the CMV disease (whether life orsight threatening) and host risk factors (D�R�, lung trans-plantation, and severe immunosuppression), an empirictherapy is begun, pending return of genotypic resistance testdata. In a high-risk clinical setting, empiric combination gan-ciclovir and foscarnet therapy is reasonable (at either partialor standard doses) (123, 124) or foscarnet alone. Alterna-tively, for more mild CMV disease, ganciclovir can be in-creased to higher than standard doses (up to 10 mg/kg twicedaily for normal renal function).

If genotypic resistance testing reveals a major UL97mutation (�5-fold increased ganciclovir resistance), a switchto foscarnet is suggested. UL97 mutations conferring lesserdegrees of resistance may permit the continued use of ganci-clovir at higher doses (125) (between 5 and 10 mg/kg twicedaily for normal renal function), but genotypic testing for aviral UL54 pol mutation is suggested. If a pol mutation ispresent that confers added ganciclovir resistance (and usuallycidofovir cross-resistance), switching to foscarnet is recommended.Because of the demonstrated frequency of ganciclovir-cidofovircross-resistance from pol mutations, cidofovir is not recom-mended as an alternate therapy for ganciclovir-resistantCMV, unless pol mutations are shown to be absent and thedisease is not clinically severe. There is little information onthe efficacy of cidofovir in SOT; its use in HSCT gave mixedresults (126). Additional guidance appears in Figure 1.

Adjunctive TherapyAdjunctive treatments, defined as those without a spe-

cific CMV antiviral drug target, have not been adequatelyevaluated. Immunoglobulins containing CMV antibodiesand adoptive infusions of CMV-specific T-cells (58) may im-prove antiviral host defenses. Several small molecule drugs,including sirolimus (127, 128), leflunomide, and artesunate(129), have shown anti-CMV effects, probably by alteringhost cell physiology to a less permissive condition for viralreplication (130). Leflunomide was reported to clear CMVviremia in a HSCT and renal transplant recipients with drug-resistant CMV (130, 131), but also to have failed in anotherHSCT recipient (132). Prolonged leflunomide treatment maybe needed to clear CMV viremia (133).

Experimental CMV Antiviral AgentsMaribavir (MBV) is an orally administered benzimid-

azole L-riboside that is a potent inhibitor of the CMV UL97kinase (134, 135). A phase II trial showed significant reduc-tion of active CMV infection when MBV was given as pro-phylaxis after HSCT (136). Phase III trials were initiated toconfirm this effect in larger groups of HSCT and liver trans-plant recipients, but they were halted when MBV was foundto have similar outcomes compared with placebo in HSCT.Because there is no known cross-resistance between currentdrugs and MBV (137), it has been used as salvage therapy forthose who have developed multidrug resistant CMV infec-tion, with too few cases to assess efficacy.

Future Research and Clinical Practice NeedsBecause of the relative infrequency of CMV drug resis-

tance, adequate prospective studies have not been performedto define the outcomes of drug-resistant CMV. Genotypicresistance testing needs to be made more widely available,with improved interpretation of the degree of resistance con-ferred to various drugs by the mutations present in a givenclinical specimen. A validated and continuously updatedpublic database of these mutations would be a valuable re-source. New therapeutic options lacking cross-resistance withcurrent drugs are needed.

Consensus RecommendationsFigure 1 explains the management of suspected ganci-

clovir resistance (III).

PEDIATRIC ISSUES IN CMV MANAGEMENTManagement of CMV infection and disease in pediatric

organ transplant recipients presents a number of specificchallenges. The pediatric group considered and adopted is-sues that were common to both children and adults, takinginto account existing guidelines (138, 139). For the purposesof this document, the pediatric age group was defined as 12years or less. It should be noted that this age cutoff will not beapplicable to all children, taking into account other factors,including body weight.

Current Burden of CMV-Associated Diseasein Children

CMV infection and disease remain important causes ofmorbidity and occasional mortality among pediatric organtransplant recipients. Data on the precise burden in pediatricorgan transplant recipients are limited, however, by widedifferences in data collection and reporting. In addition, non-uniform approaches to the laboratory diagnosis and defini-tion of CMV disease in retrospective studies affect the abilityto interpret available data. In five centers in the United States,10% to 20% of liver transplant patients experienced CMVdisease within 2 years after transplantation (140). These pa-tients had received 2 weeks of prophylaxis with ganciclovirwith or without immune globulin. A review of first-time pe-diatric lung transplant patients indicated that among at-risksubjects, the incidence of CMV viremia was 29% to 32%,whereas that of CMV pneumonitis was 20% in the first yearafter transplantation (141, 142).

Primary Risk Factors for the Development ofCMV Disease in Children

Adult and pediatric patients share similar risk factorsfor the development of CMV disease after transplantation(143). Compared with adult transplant recipients, childrenhave an increased likelihood of acquiring primary CMV in-fection because children are more often CMV naïve at thetime of transplant. Characterizing donor and recipientserostatus in children less than 18 months of age is compli-cated by the variable persistence of transplacental maternalCMV antibodies. CMV D�R� pediatric SOT recipients re-main at ongoing risk of de novo infection due to environmen-tal CMV exposures in the posttransplant period. In addition,leukocyte-reduced or CMV-negative blood products should


be considered for special populations (e.g., bowel, lungs, andhearts) and in CMV D�/R� patients. Similar to adult SOTrecipients, pediatric patients who receive antilymphocyteglobulin or OKT3 for rejection are at increased risk of CMVdisease. Of special note, the implications of starting childrenwith developing immune systems on immunosuppressionare unclear and are in need of further study, as it has beenobserved by some experts that young children may seem to bemore immunosuppressed than what would be predictedfrom the dose of immunosuppressive drugs received.

Optimal Methods for the Diagnosis of PediatricCMV Infection/Disease

The approach to the diagnosis of CMV infection/dis-ease in children is similar to that among adults (143), with afew caveats. The amount of blood obtained by venipuncturemay be limited (thus QNAT may be easier than antigenemia).In children, some invasive diagnostic procedures are moredifficult (e.g., transbronchial biopsies in young infants).

Prevention of Pediatric CMV DiseaseBoth preemptive therapy and antiviral prophylaxis are

used to prevent CMV infection in pediatric SOT recipients.Data on the use of preemptive IV or oral therapy to preventCMV disease in this population are lacking. In general, thereis more collective experience with IV ganciclovir for preemp-tive treatment in children.

Antiviral prophylaxis is more commonly used and in-cludes both IV ganciclovir and oral valganciclovir. IV ganci-clovir is usually dosed at 5 mg/kg per day; some centers startwith 10 mg/kg in two divided doses for the initial 2 weeks ofthe prophylaxis period. Prolonged IV ganciclovir (12 weeks)has been used safely in pediatric transplant recipients (144).Valganciclovir has emerged as a viable option for preventionof CMV infection in adult SOT recipients, and emerging datain pediatric patients help to address issues relating to formu-lation and pharmacokinetics (145–147). Data regarding theefficacy of valganciclovir in pediatric SOT recipients in thesesituations are still necessary, particularly due to the potentialfor inadvertently achieving low levels and the risk of ganciclo-vir resistance. Prolonged valganciclovir use has not been thesubject of randomized studies in children, but it has beenevaluated in individuals older than 16 years (88). Absorptionissues might be of particular concern in bowel transplant re-cipients. Valganciclovir use is more likely to be associatedwith prolonged courses compared with the IV route due toconvenience. This is of theoretical concern, given the knowncarcinogenicity in animals at high doses and unknown con-sequences of prolonged ganciclovir therapy in young in-fants (Product Monograph Cytovene; Genentech, formerlyHoffmann-La Roche Limited, Basel, Switzerland).

CMV immunoglobulin is sometimes used with antivi-rals for the prevention of CMV infection and disease afterpediatric organ transplantation. Evidence is often extrapo-lated from data derived from adult populations. A recentlypublished meta-analysis of randomized trials demonstrated abeneficial effect of prophylactic CMV immunoglobulin ontotal survival and prevention of CMV-associated death inSOT recipients except kidney transplant recipients (148). Theoccurrence of CMV disease was significantly less in all recip-ients receiving prophylactic CMV immunoglobulin, but it

had no effect on CMV-infections and clinically relevant rejec-tions. None of these trials compared the efficacy of CMVimmunoglobulin with ganciclovir or valganciclovir. Limitedpublished data address the potential benefit of the addition ofCMV immunoglobulin to ganciclovir in the prevention ofCMV. In one pediatric study that primarily targeted Epstein-Barr virus, the addition of CMV immunoglobulin to 2 weeksof IV ganciclovir did not seem to have a significant impact onthe development of CMV disease, although there was a trendtoward a higher 2-year CMV disease-free rate in R� children(140). In another randomized trial that also targeted Epstein-Barr virus (149), CMV infection (but not disease) developedin 18.8% of pediatric patients receiving ganciclovir alone and5.6% in those given ganciclovir with CMV immunoglobulin;this difference was not statistically significant. Despite thelack of available data, many pediatric centers currently useCMV immunoglobulin as part of their CMV preventive strat-egies. This is evidenced by a recent survey of eight pediatriclung transplant programs that indicated that 50% use CMVimmunoglobulin as a part of a CMV prevention strategy thatalso includes the use of ganciclovir (150). Overall, there are nolarge randomized trials that show CMV immunoglobulin isof benefit when standard antiviral prophylaxis is used.

Treatment of Pediatric CMV DiseaseIn the treatment of CMV disease in children, there is a

profound lack of data on which to base firm recommenda-tions, notably as this relates to the role of IV versus oral ther-apy. Many principles that guide therapy are similar to thoseamong adults and are outlined elsewhere in this document.The concept of initial treatment followed by secondary pro-phylaxis is advocated by some experts (151).

Ganciclovir Resistance in PediatricOrgan Transplant

Because of the high likelihood of CMV D�R� status inchildren, ganciclovir resistance is of significant theoreticalconcern (115). Based on data from children with severe com-bined immunodeficiency states and pediatric HSCT recipi-ents, there are anecdotal reports of the rapid emergence ofresistance to ganciclovir. There are few reports, however, de-scribing ganciclovir resistance among pediatric SOT recipi-ents. It is unclear if this is due to low resistance burden, lack ofgenerated data, or underreporting. Similar to adult patients,the currently available agents for the treatment of ganciclovir-resistant CMV in children include foscarnet and cidofovir.The use of these agents is limited by nephrotoxicity. Otherinvestigational agents, with little or no pediatric data, includeMBV, leflunomide, and artesunate.

Consensus RecommendationsWhile recognizing that the ability to generate pediatric

data is challenging, it is recommended that:

• Given the challenge of characterizing donor and recipi-ent serostatus in those less than 18 months of age, riskassessment in this age group should assume the highestrisk level for purposes of CMV prevention (III). Donorswho are less than 18 months of age should be regarded asCMV seropositive if the CMV serologic test is positive.Similarly, any CMV seropositive recipient who is less



than 18 months of age should be assumed to be seroneg-ative, as maternal antibody may account for this finding.CMV urine culture or QNAT should be obtained fromseropositive recipients less than 18 months of age, be-cause a positive result would confirm prior CMV expo-sure. Negative CMV urine culture, however, may resultfrom intermittent shedding of virus.

• In general, the principles that guide the use of prophylaxisin adults are similar in children as defined by CMV donorand recipient serostatus. Table 4 provides a suggested ap-proach to CMV prevention with antivirals�CMV immu-noglobulin in children. CMV D�R� patients are excludedgiven the low risk (�5%) of CMV disease. Recommendedregimens are largely based on expert opinion and extrapo-lation from adult studies.

• Prophylaxis is preferred over preemptive treatment for themajority of pediatric patients (III). Most experts recom-mend at least 3 months of prophylaxis. Shorter courses areused in some centers. Longer durations have been evalu-ated in adults (I) and represent acceptable alternate coursesof action for children (III). A valganciclovir-dosing algo-rithm that adjusted for body surface area and renal func-tion and which provided ganciclovir exposures similar tothose established as safe and effective in adults has beenpublished recently (146). The dosing, pharmacokinetics,and efficacy of CMV prevention using valganciclovir re-quire further study in children. Use of this agent may beconsidered for CMV prophylaxis in older children morethan 12 years of age (III).

• The initial treatment of CMV disease in children shouldbe with IV ganciclovir at a dose of 5 mg/kg every 12 hr(II-3). In situations where secondary prophylaxis isused, IV ganciclovir is preferred (5 mg/kg/day; II-3).Given the absence of prospective data, no firm recom-mendations can be made regarding the use of oral ther-apy for the treatment of CMV disease in children (III).Some experts consider oral therapy for some older chil-dren and adolescents toward the end of their treatmentcourses (III).

• CMV immunoglobulin is recommended for the treat-ment of CMV pneumonitis and enteritis in children andfor hypogammaglobulinemia (II-2). For other clinicalentities, CMV immunoglobulin is recommended on amore selective basis (III).

• Studies of the indirect effects of CMV are needed, giventhe uncertain impact in pediatrics (III).

APPENDIXThe Consensus contributors are as follows: Leaders:

Camille N. Kotton (US) and Atul Humar (Canada); diagnos-tics: Angela M. Caliendo (leader, US), Vincent Emery (UK),Irmeli Lautenschlager (Finland), Tiziana Lazzarotto (Italy),Jutta Preiksaitis (Canada), Raymund Razonable (US), andHalvor Rollag (Norway); immunology: Deepali Kumar(leader, Canada), Michael G. Ison (US), Rajiv Khanna(Australia), Oriol Manuel (Switzerland), Cecilia Soderberg-Naucler (Sweden), Martina Sester (Germany), Julian Torre-Cisneros (Spain), and Glen Westall (Australia); prevention:David R. Snydman (leader, US), Khalid Almeshari (SaudiArabia), Mark D. Pescovitz (US), Jay A. Fishman (US), AlanJardine (UK), Nassim Kamar (France), Roberta Lattes (Ar-gentina), Christophe Legendre (France), Daniele Lilleri(Italy), Carlos Lumbreras (Spain), Nicolas Mueller (Switzer-land), Elias David-Neto (Brazil), Nina Singh (US); treatment:Anders Åsberg (leader, Norway), Anders Hartmann (Nor-way), Hildebrando Leguizamon (Colombia), Miguel Mon-tejo (Spain), Patricia Munoz (Spain), Dino Sgarabotto(Italy), and Huseyin Toz (Turkey); resistance: Sunwen Chou(leader, US), Fausto Baldanti (Italy), Guy Boivin (Canada),Ajit Limaye (US), and Nell Lurain (US); pediatrics: UptonAllen (leader, Canada), Lara Danziger-Isakov (US), and Mi-chael Green (US).

ACKNOWLEDGMENTSThe CMV Consensus Conference was organized by The

Infectious Diseases Section of The Transplantation Society. Anindependent, nonrestricted grant from Roche made this confer-

TABLE 4. Recommended regimens for CMV prevention in children

Risk categoriesRecommended regimen (s)

(see text for doses)Alternative regimen(s)

(see text for doses)

Lower (R� renal transplants) IV ganciclovir �2 wk followed byPO valganciclovira �10 wk

IV ganciclovir �12 wk

Some centers use 2–4 wk of prophylaxis

Intermediate (R� liverb and heart transplants) IV ganciclovir �12 wk IV ganciclovir �2 wk followed by POvalganciclovira �10 wk

Some centers use 2–4 wk of prophylaxis

Higher (All D�/R� transplants and R� lungand small bowelc transplants)

IV ganciclovir �12 wk Some centers use 2–4 wk of prophylaxis,and some centers extend prophylaxisto 6 mo

Some experts recommend CMV immunoglobulin for intermediate and higher risk recipients, but there are no randomized studies indicating that CMVimmunoglobulin is any better than ganciclovir or valganciclovir alone. When used, it is more consistently given to D�R� small bowel, lung, and hearttransplant recipients The regimens above do not imply an exclusive course of action. CMV D�R� patients are excluded given the low risk (�5%) of CMVdisease.

a Assumes the child is able to take oral medication; otherwise the default option is IV ganciclovir.b Some experts place R� liver recipients in the lowest risk group.c Some experts place R� small bowel recipients in the intermediate risk group.CMV, cytomegalovirus; IV, intravenous; PO, oral.


ence possible. The authors thank Filomena Picciano, FrankLindo Verissimo, and Catherin Parker of The TransplantationSociety for their administrative support.

CMV Consensus Meeting participants’ conflict of interest:Upton Allen, Hospital for Sick Children: grant application toHoffmann—La Roche from 2007 to 2008. Khalid Almeshari,King Faisal Specialist Hospital & Research Center: consultantfor Genzyme for 1 year and consultant for Wyeth for 3 years.Anders Åsberg, University of Oslo: consultant for Roche from2004 to 2008. Fausto Baldanti, Fondazione IRCCS PoliclinicoSan Matteo: declares no conflict of interest. Guy Boivin, Centrede recherche du CHUL: grant application to Roche from 2001 to2008. Angela Caliendo, Emory University School of Medicine:Scientific advisor for Roche Molecular Diagnostics, Nanogen,Siemens, and Qiagen. Sunwen Chou, VA Medical Center:speaker for Robert Michael Education Institute 2007 to 2008,research contract with ViroPharma for resistance testing servicesdone. Lara Danziger- Isakov,; Cleveland Clinic: supported bygrant CSL Behring from 2004 to 2008. Elias David-Neto, Uni-versity of Sao Paulo. Vincent Emery, University College London(UCL), Centre for Virology: consultant and speaker for Rochefor 10 years and consultant and speaker for ViroPharma for 1year. Jay A. Fishman, Massachussetts General Hospital: SAB forPrimera since 2007 and speaker for Roche in 2008. MichaelGreen, Division of Infectious Diseases, Children’s Hospital ofPittsburgh of UPMC. Anders Hartmann, Rikshospitalet Uni-versity Hospital. Atul Humar, University of Alberta: supportedby grant from Roche from 2006 to 2009, honoraria from Rochein 2008, and speaker for ViroPharma in 2008. Michael Ison,Northwestern University: speaker for Viracor since 2007,speaker for Abbott molecular in 2008, PI for Roche since 2005, PIfor Biocryst and ViroPharma since 2006, PI for Pfizer since2007, and PI for Adma since 2008. Alan Jardine, BHF Cardio-vascular Research Centre: consultant for Roche since 2000, con-sultant for Novartis since 1996, consultant for AstraZeneca since2003, consultant and speaker for Wyeth since 2002, and speakerfor Astellas since 2008. Nassim Kamar, Department of Nephrol-ogy, Dialysis & Multi-Organ Transplantation, ToulouseUniversity Hospital: honoraria from Roche. Rajiv Khanna,Queensland Institute of Medical Research: consultant for Celles-tis in 2005. Camille Kotton, Massachusetts General Hospital:honoraria from ViroPharma in 2009. Deepali Kumar, Univer-sity of Alberta: research funding from Hoffmann-LaRoche andCellestis Inc. Roberta Lattes: declares no conflict of interest.Irmeli Lautenschlager, Helsinki University Central Hospital:declares no conflict of interest. Tiziana Lazzarotto, Bologna St.Orsola Malpighi General Hospital: declares no conflict of inter-est. Christophe Legendre, Hopital Necker: consultant for Roche.Hildebrando Leguizamon S., Columbiana de Transplantes fromColombia: declares no conflict of interest. Daniele Lilleri,Fondazione IRCCS Policlinico San Matteo: declares no conflictof interest. Ajit Limaye, University of Washington: speaker forRobert Michael Education Institute in 2008 and research con-tract from Roche and ViroPharma. Carlos Lumbraras, Univer-sidad Europea de Madrid: declares no conflict of interest. NellLurain, Department of Immunology/Microbiology, Rush Uni-versity Medical Center: consultant for Abbott from 2006 to 2008.Oriol Manuel, University Hospital of Lausanne (CHUV): TIDfellowship from Roche for 2 years (2006). Miguel Montejo, Hos-pital de Cruces: declares no conflict of interest. Nicolas J. Muel-ler, Division of Infectious Diseases, University Hospital Zurich:

declares no conflict of interest. Patricia Munoz; Hospital Gen-eral Universitario Gregorio Maranon: declares no conflict of in-terest. Mark Pescovitz, Indiana University: PI, consultant, andspeaker for Roche for 10 years, PI and consultant for Viro-Pharma for 3 years, and consultant for Vical for 1 year. Jutta K.Preiksaitis, Provincial Laboratory for Public Health: declares noconflict of interest. Raymund R. Razonable, Mayo Clinic: sup-ported by Roche in 2008 and PI for ViroPharma since 2008.Halvor Rollag, Institute of Microbiology, Rikshospitalet: mem-ber of Victor Steering Committee for Roche since 2004. MartinaSester, Department of Transplant and Infection Immunology,University of Saarland: declares no conflict of interest. DinoSgarabotto, Padua General Hospital: speaker for Roche andBayer for 3 year and, speaker for Pfizer for 4 year. Nina Singh,Pittsburgh VA Medical Center/University of Pittsburgh MedicalCenter: data safety monitoring board for Viropharma study1263-300. David R. Snydman, Tufts Medical Center: consultantfor CSL Behring since 2008 and supported by Roche from 2003to 2005. Cecilia Soderberg-Naucler, Karolinska Institutet: in-vestigational grant and occasional speaker for Roche for 6 yearand speaker honorarium for CME in 2008. Julian Torres-Cisneros, UGC of Infectious Disease, Hospital UniversitarioReina Sofia: speaker bureau and supported by Roche from 2007to 2009. Huseyin Toz, Division of Nephrology, Ege UniversityMedical School: declares no conflict of interest. Glen Westall,Alfred Hospital: supported by Cellestis for 2 year, consultant forCSC in 2007, and speaker bureau from Roche in 2008.

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