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A Guide for the Perplexed

Santos, Carlos A.Q. MD, MPHS1; Brennan, Daniel C. MD2

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doi: 10.1097/TP.0000000000002203
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Cytomegalovirus (CMV) infection remains one of the most common opportunistic infections in solid organ transplantation.1 Before the availability of effective antiviral agents, the only treatment was dramatic reduction or complete withdrawal of immunosuppression. This risked rejection and return to dialysis in kidney transplant recipients, and death for other solid organ transplant patients. The development of ganciclovir and then valganciclovir has led to major advances in the prevention and treatment of CMV in solid organ transplant recipients, and has lulled many transplant practitioners into thinking that CMV is more of a nuisance rather than a life-threatening illness.

Cytomegalovirus, however, is far from just being a nuisance. Cytomegalovirus disease after stopping preventive therapy remains a frequent complication and is associated with allograft failure and death.2,3 Moreover, indirect effects of CMV infection, such as upregulation of HLA antigen expression, predisposition to other opportunistic infections and sepsis, and chronic allograft dysfunction, are well characterized.4 Cytomegalovirus is a lifelong infection, and though often latent and out of sight is not gone.

Although the virus is more manageable in the current era, many questions remain. How can delayed-onset CMV disease be prevented? Is it through active monitoring for viral replication and resultant preemptive treatment, or measurement of CMV-specific immune responses that can identify patients at higher risk of developing CMV infection? What is the comparative effectiveness of prophylactic versus preemptive therapy in real-world settings? Does this differ by serostatus, organ transplanted, immunosuppression and country? What is the viral DNAemia threshold that should be used to initiate preemptive treatment? How should CMV disease in the absence of DNAemia be monitored? What is the role of letermovir, a novel terminase inhibitor, in the management of CMV among solid organ transplant recipients? Is it time we remembered our past and recognize that CMV is an infection that reflects excessive immunosuppression and that reduction of immunosuppression is central to its treatment?

In this issue of Transplantation, Kotton et al5 answer these questions and many others in the Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation. It is a comprehensive review from some of the foremost researchers and clinicians in the field that very clearly synthesizes information on the prevention and treatment of CMV in adult and pediatric settings, as well as advances in diagnostics, immunologic monitoring and new antiviral therapies. Particularly illuminating are its discussions on challenges to developing standard viral load thresholds to initiate preemptive treatment, immune monitoring assays which measure CMV-specific T-cell responses, novel antiviral therapies such as letermovir, maribavir, and brincidofovir, and management of drug-resistant CMV. It also emphasizes that valganciclovir dosing should be based on the estimated glomerular filtration rate calculated using chronic kidney disease-epidemiology or modification of diet in renal disease equations rather than Cockcroft-Gault which overestimates estimated glomerular filtration rate in settings of chronic renal insufficiency and could lead to overdosing and toxicity. Its discussions on future directions are prescient and can be used to inform research agendas in academia and industry.

We believe the Guidelines could have emphasized more strongly that CMV is a sign of overimmunosuppression and that reducing immune compromise is germane to its management. We have shown that stopping the antimetabolite is an important component of CMV management even in the era of effective antiviral therapy and does not increase the risk of developing donor specific antibodies and rejection as long as the calcineurin inhibitor is not too aggressively decreased at the same time.6,7 Moreover, decreasing immunosuppression by stopping the antimetabolite has beneficial effects by enabling better control of other typically latent infections such as Epstein-Barr virus, herpes simplex virus, and BK.8 Indeed, infectious disease physicians should work closely with transplant practitioners to reduce immunosuppression for optimal management of opportunistic infections.

We also think that although advances in measuring CMV-specific T cell responses are intriguing, more studies demonstrating safety and cost-effectiveness of changing management based on results of immune assays are needed before these tests can be adapted widely. Two assays are now more commonly available: Quantiferon-CMV, an enzyme-linked immunosorbent assay-based interferon-gamma release assay detecting CD8 T cells after stimulation with CMV peptides; and ELISpot, which quantifies both CD4 and CD8 T cells producing interferon-gamma in response to IE1 and pp65. We await studies with derivation cohorts showing that use of these assays improves on current predictors for CMV infection and disease, and validation studies demonstrating replicability in other settings.

The current guidelines and its previous iterations have recommended against using CMV prophylaxis in donor/recipient seronegative (D−/R−) patients given their minimal risk. However, we have shown in a large pharmacoepidemiologic study of kidney transplant recipients that 1 in 4 transplant centers in the United States prescribe valganciclovir to more than 60% of their D−/R− patients for a median of 2 months, indicating considerable departure from expert recommendations.9 These findings highlight gaps between guidelines and practice, and emphasize the considerable work needed to ensure implementation of evidence-based recommendations in real-world settings.

The guidelines could have benefited from using consensus building methodology that ensures that all viewpoints are heard. Such methods were used in the Standardized Outcomes in Nephrology-Kidney Transplantation initiative, which convened patients, caregivers, and health professionals, and used focus groups, iterative Delphi surveys, Likert scales and qualitative data analysis to arrive at core outcomes by consensus.10 The methods used in Standardized Outcomes in Nephrology-Kidney Transplantation have the advantage of preventing 1 strong group or individual from controlling the guideline and can result in recommendations that more truly reflect consensus.

In summary, CMV still poses challenges to transplantation in the current era. This Consensus Statement on CMV management in transplant recipients is a timely and important update, and superbly defines the state of the field. We would add that management of immunosuppression in CMV infection is as important as antiviral therapy, and that efforts are needed to ensure that guidelines reflecting best evidence are widely adapted in real-world settings.


1. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013;45:260–271.
2. Arthurs SK, Eid AJ, Pedersen RA, et al. Delayed-onset primary cytomegalovirus disease and the risk of allograft failure and mortality after kidney transplantation. Clin Infect Dis. 2008;46:840–846.
3. Santos CA, Brennan DC, Chapman WC, et al. Delayed-onset cytomegalovirus disease coded during hospital readmission in a multicenter, retrospective cohort of liver transplant recipients. Liver Transpl. 2015;21:581–590.
4. Borchers AT, Perez R, Kaysen G, et al. Role of cytomegalovirus infection in allograft rejection: a review of possible mechanisms. Transpl Immunol. 1999;7:75–82.
5. Kotton C, Kumar D, Chou S, et al. The third international consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation. 2018;102:900–931.
6. Spinner ML, Saab G, Casabar E, et al. Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes. Transplantation. 2010;90:412–418.
7. Hricik DE, Formica RN, Nickerson P, et al. Adverse outcomes of tacrolimus withdrawal in immune-quiescent kidney transplant recipients. J Am Soc Nephrol. 2015;26:3114–3122.
8. Seifert ME, Gunasekaran M, Horwedel TA, et al. Polyomavirus reactivation and immune responses to kidney-specific self-antigens in transplantation. J Am Soc Nephrol. 2017;28:1314–1325.
9. Santos CA, Brennan DC, Saeed MJ, et al. Pharmacoepidemiology of cytomegalovirus prophylaxis in a large retrospective cohort of kidney transplant recipients with medicare part D coverage. Clin Transplant. 2016;30:435–444.
10. Tong A, Gill J, Budde K, et al. Toward establishing core outcome domains for trials in kidney transplantation: report of the standardized outcomes in Nephrology-Kidney Transplantation Consensus Workshops. Transplantation. 2017;101:1887–1896.
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