GSK1904529A In this clinical context measures of cell
In this clinical context, measures of cell-mediated immune response to CMV have been evaluated. The QuantiFERON-CMV assay (QFN-CMV; Qiagen, Germany) which measures predominantly CD8+ T-cell responses to CMV by an in-tube IFN-gamma release technique is commercially available in some regions.1, 2 Consensus international guidelines acknowledge the role of immunological monitoring, such as with the QFN-CMV, as an adjunct to predict risk of viraemia and disease in the post-prophylaxis and pre-emptive treatment setting. Despite this, only 12% of transplant centres in an international survey were using immune based monitoring. The QFN-CMV assay has previously been shown to be effective at predicting a patient's risk of CMV disease when measured pre-transplant, at the end of prophylaxis and during pre-emptive treatment strategies.3, 4, 8, 9, 10, 12, 13, 14, 16 The lack of interventional studies had previously been cited as a rationale for the lack of GSK1904529A of this assay into clinical practice; however, a recent small study has shown utility of the assay in decisions regarding the need for ongoing prophylaxis following treatment of CMV infection. Previous studies examining the utility of the QFN-CMV have not included regular virological monitoring following cessation of prophylaxis, so the natural history of low grade viraemia detected by current assays with high analytical sensitivity in relation to CMV immunity remains unclear. As frequent viral monitoring is part of routine post-transplant care in Western Australia, we examined the relationships between early post-prophylaxis CMV-specific immune responses as measured by the QFN-CMV assay, subsequent development of CMV viraemia or disease and requirement for pre-emptive antiviral treatment in this setting.
Materials and methods
Discussion Several studies have explored the utility of the QFN-CMV assay in predicting late onset CMV disease following renal, lung, liver and cardiac transplantation. These studies have occurred across centres with varying approaches to CMV prophylaxis and viral monitoring. We have shown that in Western Australian solid organ transplantation recipients, tissue-invasive disease due to CMV reactivation is extremely uncommon but the development of low level CMV viraemia is common, occurring in 61% of our transplant recipients post-transplantation. We found that CMV seropositivity was the single biggest determinant of any level CMV viraemia >20 copies/mL post-transplant, and as in healthy blood donors, this was also associated with positive rather than negative QFN-CMV responses. However, previous studies have found a higher incidence of CMV viraemia in D+R– compared to R+ solid organ transplants after prophylaxis. We postulate that the extended duration of prophylaxis had an effect to lower the incidence. Additionally, the more potently immunosuppressed thoracic transplant recipients were over-represented among the R+ transplants. Using CMV viraemia alone as the outcome measure in this study largely identified patients with background CMV infection and chronic antigen-driven memory responses. However, the only two patients in the study cohort who did develop tissue invasive disease despite a generally aggressive approach to prophylaxis and viral monitoring had negative QFN-CMV responses. The average viral load was higher and time to first viraemia shorter among those with negative QFN-CMV responses in longitudinal analyses, but we could not detect a statistically significant difference, noting very small numbers of patients with high level viraemia and the common use of antiviral medication to supress viraemia without evidence of organ-invasive disease. Among those patients with natural decline or stability of low grade asymptomatic viraemia, the vast majority had intact CMV immunity. These results are consistent with current models of CMV persistence and reactivation. In immunocompetent individuals, CMV elicits a vigorous innate and adaptive immune response. Adaptive responses include induction of strongly neutralising humoral responses against antigens required for systemic dissemination via endothelial, epithelial and myeloid cells after primary infection. Induction of a broadly targeted cellular immune response limits viral replication and recruits progressively increasing numbers of CMV-specific CD4 and CD8 T cells to the memory pool. Despite up to 10% of the of the total antigen-specific T-cell memory being CMV-specific and this proportion inflating through life, the virus is not eliminated completely but rather maintained in a state of long-term latency in a dynamic interaction with host immune memory. CMV-specific effector memory cells have a dominant Th1 functional phenotype with the capacity to rapidly release IFN-γ upon T-cell receptor mediated activation in vivo when there is viral reactivation or in vitro as demonstrated in the QFN-CMV assay. However, it is not clear what frequency of CMV-specific T cells are required to maintain viral control and it is notable that many cases of viral reactivation, as indicated by low grade viraemia in the post-transplantation setting, can be controlled without antiviral drugs, presumably as a result of re-stimulated CMV-specific cellular immunity.