The Ability of a Cytomegalovirus ELISPOT Assay to Predict Outcome of Low-Level CMV Reactivation in Hematopoietic Cell Transplant Recipients (original) (raw)

2018, The Journal of Infectious Diseases

Background. Cytomegalovirus (CMV) infections in hematopoietic cell transplant (HCT) recipients cause substantial morbidity and mortality. CMV cell-mediated immunity (CMV-CMI) can be determined by levels of interferon gamma (IFN-γ) production using an enzyme-linked immunospot (ELISPOT) CMV assay (T-SPOT.CMV assay). In this study, we evaluated the ability of this assay to predict the outcome of low-level CMV reactivation in HCT recipients. Methods. We followed 55 HCT recipients with low-level CMV reactivation up to 8 weeks from enrollment. Progression to clinically significant CMV infection (CS-CMVi) was defined as a CMV load >1000 IU/mL or > 500 IU/mL in patients receiving matched related/autologous or matched unrelated transplants, respectively, and initiation of antiviral treatment. Results. Progression to CS-CMVi occurred in 31 (56%) of the HCT recipients. Spot counts of CMV-specific pp65 and IE1 antigens were significantly lower in patients who had CS-CMVi than in patients who did not. On multivariate analysis, the ELISPOT CMV responses and steroids use were the only predictors of progression to CS-CMVi. Conclusions. A strong association between low CMV-CMI and progression to CS-CMVi was observed in HCT recipients. The implementation of serial monitoring of CMV-CMI may identify patients at risk of progression to CS-CMVi that require antiviral therapy. Keywords. cytomegalovirus; cell-mediated immunity; ELISPOT assay; low-level CMV reactivation; hematopoietic stem cell transplant. Cytomegalovirus (CMV) infection may lead to life-threatening complications in immunocompromised individuals, including recipients of hematopoietic cell transplantation (HCT) [1]. In particular, patients who are CMV seropositive (IgG positive) are considered to be at high risk for CMV reactivation [2, 3]. Around 5% of allogeneic HCT (allo-HCT) recipients who are CMV seropositive develop CMV end-organ disease [4, 5]. In some studies, CMV infections were associated with graft failure, graft-versus-host disease (GVHD), and secondary bacterial and fungal infections after transplantation [6, 7]. Preemptive therapy has been the main strategy employed for at least a decade for prevention of CMV end-organ disease. It consists of initiating anti-CMV drugs once CMV is detected at a certain threshold in whole blood or plasma of allo-HCT recipients [8]. The specific threshold for therapy initiation is not well defined and is center and host specific. Considering the toxic effects of the available antiviral agents, this strategy could be detrimental for patients deemed at low risk for CMV end-organ disease and with CMV load <1000 IU/mL [8]. CMV cell-mediated immunity (CMV-CMI) is essential to control CMV replication and prevent progression to CMV end-organ disease in patients with prior exposure [9, 10]. CMV-CMI is assessed by the interaction of both CD4 + and CD8 + T cells and CD8 + T-cell production of interferon gamma (IFN-γ) and other cytokines in the presence of CMV. The enzyme-linked immunospot (ELISPOT) CMV assay (T-SPOT.CMV assay; Oxford Diagnostic Laboratories, Memphis, TN), allows the evaluation of CD4 + and CD8 + T-cell immunity by an ex vivo stimulation of both CD4 + and CD8 + T cells with CMV antigens reacting with human leukocyte antigen class I haplotypes, thus triggering the production and release of IFN-γ. Patients with latent CMV infection have CD4 + and CD8 + T cells that recognize these antigens and secrete IFN-γ in response, and detecting this process by a modified version of the traditional enzyme-linked immunosorbent assay (ELISA) forms the basis of the assay [11, 12]. The utility of this ELISPOT CMV assay has been studied in the solid-organ transplant (SOT) population [13, 14]. In a study of heart transplant recipients, it was shown that early identified high responders (spot count [SPC] >100 per 250 000 cells) maintained a high