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  • The immune control of CMV replication in vivo


    The immune control of CMV replication in vivo is primarily driven by the T-cell-mediated response, a characteristic that has been proposed as a tool to individualize and therefore to optimize antiviral treatment [6], [7], and it has been associated with spontaneous clearance of CMV viraemia in patients at high (D+/R–) and intermediate risk (R+) [7], [8], [9], [10], [11], [12]. Although the majority of SOT patients are R+, this is precisely the least studied 2'-O-Methyl-ATP and the few published reports include an insufficient sample size [13], [14]. R+ patients have a significant incidence of CMV DNAaemia (around 50%) and CMV disease (around 20%) after transplantation [15], [16]. We previously reported in Mena-Romo et al. [10] that having a positive T-cell immune response at 2 weeks and 4 weeks after transplantation independently reduced the risk of requiring early treatment and developing high-level viraemia. In that study, after a mid-term analysis and based on the unexpected high number of patients with no CMV-specific T-cell immune response at 2 weeks after transplantation, we initiated the study of the T-cell immune response before transplantation. However, the small number of patients with a pretransplant sample prevented a multivariate study to confirm if CMV-specific immunity was an independent protective factor for CMV disease [10]. Other authors reached only partial conclusions, and had little clinical utility since the CD8 T-cell response was characterized in small cohorts or with no stratification based on pretransplant serology, induction therapy or early treatment administration [17], [18], [19], [20].
    Patients and methods
    Discussion Pretransplant CMV serology has been used to establish a patient's risk for developing CMV infection, which guides the prophylactic approach for CMV infection in SOT recipients [3]. Several findings in the present study suggest that using CMV pretransplant serology might be insufficient. First, only one-third of the SOT recipients with pretransplant positive serology for CMV also had CMV-specific T-cell immunity before transplantation. This proportion varied among different studies, ranging between 31% and 70% [10], [11], [21], [24], [25], [26], probably due to differences in the methods used for determining T-cell mediated immunity and the cut-offs established. In fact, the absence of standardization between centres and the complexity of the assays remain a limitation for the assessment of the CMV-specific T-cell immune response. Second, we found that the evolution of the CMV specific T-cell response after transplantation was clearly related with having immunity before transplantation. In fact, all patients with pretransplant CMV specific T-cell responses also had immunity during the follow-up, and it was detected within the first 2 months after transplantation. These findings confirm our previously reported results performed in a smaller cohort of R+ patients [10]. Conversely, the evolution of the CMV-specific immune response in patients with no pretransplant immunity resembled that of CMV high-risk recipients (R–/D+) [7], [27], since only 46% of the patients had a T-cell response after transplantation, and was detected later at a median of 3 months after the transplant. In addition to CMV-specific T-cell immunity, other factors need to be considered in order to establish the risk of CMV infection in SOT recipients. During the past few decades, advances in the immunosuppressive regimens and treatment of acute rejection episodes have significantly improved allograft survival after the transplant [28], [29], [30]. However, acute rejection therapy increases the risk of opportunistic infections, such as herpes virus infections [31]. Patients with therapy for acute rejection have a 13-fold higher risk of receiving CMV pre-emptive therapy [32]. Induction therapy with thymoglobulin has also been associated with CMV disease, and patients with thymoglobulin receive prophylaxis for CMV infection [1]. However, the use of basiliximab does not produce any change in the CMV prophylaxis strategy [1]. Although patients receiving thymoglobulin were excluded in this study, we found that induction with basiliximab increased by threefold the risk of requiring pre-emptive therapy.