Background Antiviral prophylaxis is recommended in cytomegalovirus (CMV)-seropositive kidney transplant (KT) recipients receiving antithymocyte globulin (ATG) as induction. An alternative strategy of premature discontinuation of prophylaxis after CMV-specific cell-mediated immunity (CMV-CMI) recovery (immunoguided prevention) has not been studied. The aim of this study was to evaluate whether it is effective and safe to discontinue prophylaxis when CMV-CMI is detected and to continue with preemptive therapy. Methods In this open-label, non-inferiority clinical trial, patients were randomized 1:1 to follow immunoguided strategy, receiving prophylaxis (valganciclovir 900 mg daily) until CMV-CMI recovery or to receive fixed-duration prophylaxis until day +90. After prophylaxis, preemptive therapy (valganciclovir 900 mg twice daily) was indicated in both arms until month 6. The primary and secondary outcomes were incidence of CMV disease and replication, respectively, within the first 12 months. Desirability of outcome ranking (DOOR) assessed two deleterious events (CMV disease/replication and neutropenia). Results A total of 150 CMV-seropositive KT recipients were randomly assigned. There was no difference in the incidence of CMV disease (0% vs. 2.7%; P = 0.149) and replication (17.1% vs. 13.5%; log-rank test, P = 0.422) between both arms. Incidence of neutropenia was lower in the immunoguided arm (9.2% vs. 37.8%; OR, 6.0; P < 0.001). A total of 66.1% of patients in the immunoguided arm showed a better DOOR, indicating a greater likelihood of a better outcome. Conclusions Prophylaxis can be prematurely discontinued in CMV-seropositive KT patients receiving ATG when CMV-CMI is recovered since no significant increase in the incidence of CMV replication or disease is observed.

The QuantiFERON-CMV (QF) assay measures cell-mediated immunity against cytomegalovirus (CMV-CMI), which is particularly useful in individuals susceptible to CMV infection such as transplant patients. A positive QF result identifies patients that are better protected against CMV infection. However, the significance of a negative QF result in CMV-seropositive individuals needs to be clarified. CMV-CMI was analyzed in healthy subjects using the QF assay, and, in parallel, the Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood (FASCIA). FASCIA assay measures T-cell proliferation using CMV lysate as stimulus whereas QF assay use a mix of peptides. A total of 93 healthy volunteers were enrolled, and 13/71 CMV-seropositive individuals (18.3%) showed humoral/ cellular discordance using QF assay (CMV+ QF−). Interestingly, with FASCIA assay CD4+ and CD8+ T-cell proliferations were lower in CMV+ QF− than in CMV+ QF+ individuals. Furthermore, CMV+ QF− volunteers had a lower level of anti-CMV IgG than CMV+ QF+ subjects. Discordant CMV+ QF− volunteers can be defined as low responder individuals since they show lower CMV-specific humoral and cellular immune responses in comparison to CMV+ QF+ individuals. Immune discordance shows the high heterogeneity of immunity to CMV in healthy subjects.In the last years, a variety of assays have been developed to measure cell-mediated immunity against cytomegalovirus (CMV-CMI), where the basic principle is the CMV-specific stimulation of T cells for 6-24 hours in cell culture 1,2 . These techniques have been shown to be particularly useful in individuals such as transplant patients who are susceptible to CMV infection, since they identify who is better protected against CMV infection after transplantation, as has been reported in international guidelines on the management of CMV in solid organ or stem cell transplantation 3,4 . Specifically, the detection of CMV-CMI at pretransplant or posttransplant using QuantiFERON-CMV (QF), ELISpot or intracellular cytokine staining has been associated with a lower risk of CMV infection, not only in observational studies 5-9 .Although most individuals show an agreement between CMV-serostatus and CMV-CMI, some of them have a discordance. Therefore, there are CMV-seropositive individuals without CMV-CMI, as well as CMV-seronegative individuals with protective CMV-CMI. Discordant individuals have been reported in both transplant patients and healthy virus carriers 8-12 .The QuantiFERON-CMV is an in vitro assay that measures CMV-CMI by quantifying IFNG released by CD8+ T cells after stimulation with a pool of HLA-restricted CMV peptides 13 . In some observational studies carried out in our group in solid organ transplant patients we found that 20-25% of CMV-seropositive transplant open Scientific RepoRtS | (2020) 10:7194 | https://doi.org/10.1038/s41598-020-64133-x www.nature.com/scientificreports www.nature.com/scientificreports/ candidates lacked CMV-CMI response using the QF assay, and they showed a higher risk of p...

Background This is a prospective, multicenter, observational study in cytomegalovirus (CMV)-seropositive kidney transplant recipients with pretransplant CMV-specific cell-mediated immunity (CMV-CMI) receiving antithymocyte globulin (ATG). We aimed to investigate posttransplant CMV-CMI over time as well as the impact of the dose-dependent ATG. Methods CMV-CMI was assessed at days +30, +45, +60 and +90 after transplantation with the QuantiFERON-CMV assay. A “Reactive” result (IFNG ≥0.2 UI/mL) indicated a positive CMV-CMI. Results A total of 78 positive CMV-CMI patients were enrolled in the study, of which 59.5% had a positive CMV-CMI at day +30 and 82.7% at day +90. Multivariate logistic regression analysis showed that the ATG dose was not associated with positive CMV-CMI at any point. However, pretransplant IFNG level (>12 IU/mL vs. ≤12 IU/mL) was associated with having positive CMV-CMI at day +30 (OR 12.9; 95% CI 3.1-53.3; P < .001). In addition, all the patients who did not recover CMV-CMI at day +90 had a pretransplant IFNG level ≤12 IU/mL. Conclusion More than half of CMV-seropositive kidney transplant recipients receiving ATG recover (or maintain) CMV-CMI by the first month after transplantation The pretransplant IFNG level, but not the ATG dose, shows a strong association with the kinetics of this recovery.