Implementation of Cytomegalovirus Cell–mediated Immune Monitoring in the Routine Clinical Practice for Low-risk Kidney Transplant Recipients: Are we There yet?

The recent publication of the Fourth International Consensus Guidelines for the Management of Cytomegalovirus (CMV) in Solid Organ Transplantation highlights the tremendous advances achieved in recent years in the diagnosis, prevention, and treatment of CMV infection in kidney transplant recipients.1 CMV infection has evolved from a life-threatening condition into an infectious complication that is generally treated in the outpatient setting and is associated with good outcomes in most cases. A small group of high-risk patients remains, namely CMV seronegative patients receiving an organ from a CMV seropositive donor (D+/R–), in whom primary infection may be associated with frequent relapse and protracted viral replication. However, most kidney transplant recipients (from 50% to 95% depending on the geographical area) are CMV seropositive (R+), in whom the incidence of CMV disease is low, particularly among those not receiving antithymocyte globulins (ATG). Until recently, no reliable markers were available to determine which R+ patients remain at risk of CMV replication (and might benefit from similar preventive strategies to those used in D+/R–) or, more importantly, to identify those patients at sufficiently low risk who may not require any preventive strategy at all. In this context, CMV cell–mediated immunity assays have emerged as a potential tool for dynamically evaluating the risk of CMV replication, a strategy now referred to as immune monitoring. Several observational studies have shown that these assays have good positive predictive value (ie, when the test is positive, the risk of CMV infection is low), but low negative predictive value (ie, when the test is negative, the ability to predict CMV infection is low). Subsequent randomized clinical trials, including high-risk D+/R– patients and R+ patients receiving ATG, have confirmed that immune monitoring has little value in D+/R– patients, as most of these patients do not mount detectable immunity during the first months posttransplant. However, it allows early discontinuation of prophylaxis in a significant number of R+ patients receiving ATG2,3 in whom the use of immune monitoring is now recommended by the International Consensus Guidelines.1 Additional data are needed to assess the performance of these assays in patients perceived to be at very low risk for CMV complications, namely CMV R+ patients not receiving ATG. In this issue of Transplantation, Caso et al4 presented their clinical experience with a commercial CMV cell–mediated immune assay (the Quantiferon-CMV assay) to guide the choice of antiviral preventive strategy in a cohort of CMV R+ kidney transplant recipients without ATG. In brief, a Quantiferon-CMV assay was performed within the first 2 wk posttransplant. Patients with a reactive test were considered low risk and were managed with a preemptive approach, whereas those with a negative test were considered high risk and received antiviral prophylaxis. Outcomes for CMV infection and disease were compared with those of a historical cohort from the same institution that followed a preemptive approach. The main objective of the study was to identify patients at high risk who would benefit from antiviral prophylaxis. Although approximately 20% of patients had a negative Quantiferon-CMV assay and received antiviral prophylaxis, the incidence of CMV infection requiring antiviral therapy (the primary outcome) was not different between groups. The incidence of CMV disease was lower in the intervention group, although absolute numbers were small (9 versus 2 cases). Do these results mean that CMV cell–mediated tests have no role in low-risk CMV R+ kidney transplant recipients? Several points warrant further discussion and may partially explain these findings. First, because the intervention affected only about one-fifth of patients (ie, 100% of the historical cohort and 80% of the intervention cohort were still followed by a preemptive approach), the study may have been underpowered to detect significant differences in CMV infection rates. Second, because no immune monitoring was performed in the historical cohort, it is unclear whether the cohorts were fully comparable or whether residual confounding partially explains the higher incidence of CMV disease in the historical cohort. Third, the type of assay used may have an impact on the findings, as previous data showed differences between the Quantiferon-CMV and ELISpot assays. Particularly, ELISpot assays allow stratification of CMV risk according to whether a detectable interferon response is observed against none, 1 or 2 antigens, and have shown appropriate predictive value for detecting patients at low risk.5 It is unclear whether the performance of the Quantiferon-CMV assay in this setting is suboptimal, and whether using other interferon-γ levels thresholds, adding clinical predictors (such as age or type of donor), or delaying the assay at a later time point (ie, 4 wk posttransplant) may improve the predictive value of the test.6,7 Finally, these assays appear to perform better in predicting the risk of CMV disease, a more robust endpoint, than asymptomatic CMV replication. This raises the question of whether patients with a reactive Quantiferon-CMV assay may be able to spontaneously control CMV replication without requiring preemptive antiviral therapy. The study by Caso et al indirectly points toward another important issue when discussing immune monitoring: how feasible and cost-effective is the implementation of CMV cell–mediated immunity testing in the transplant setting4,6? Commercial cell-mediated immune assays are not available in all countries, raising concerns regarding their widespread implementation in routine practice. In the present study, the great majority of tests yielded interpretable results, and the intervention was timely and followed the protocol in most patients, suggesting that feasibility was not a major concern. Finally, investigators are encouraged to add cost-effectiveness analyses when assessing the efficacy and safety of CMV immune monitoring in clinical trials. In conclusion, the study of Caso et al expands our understanding of CMV immune monitoring by highlighting its advantages and limitations in low-risk transplant recipients. These results support conducting additional pragmatic clinical trials evaluating different assays across at-risk transplant populations.