Diagnostic utility of monitoring cytomegalovirus-specific immunity by QuantiFERON-cytomegalovirus assay in kidney transplant recipients

Abstract

BackgroundDespite universal prophylaxis, late cytomegalovirus (CMV) infection occurs in a high proportion of kidney transplant recipients. We evaluated whether a specific viral T-cell response allows for the better identification of recipients who are at high risk of CMV infection after prophylaxis withdrawal.MethodsWe conducted a prospective study in 19 pretransplant anti-CMV seronegative kidney graft recipients R- (18 from seropositive donors [D+] and one from a seronegative donor [D-]) and 67 seropositive recipients R(+) (59 from seropositive donors and eight from seronegative donors) who received antiviral prophylaxis with valganciclovir. The QuantiFERON-CMV (QF-CMV) assay was performed within the first and third months after transplantation. Blood samples were monitored for CMV DNAemia using a commercial quantitative nucleic acid amplification test (QNAT) that was calibrated to the World Health Organization International Standard.ResultsTwenty-one of the 86 patients (24%) developed CMV viremia after prophylaxis withdrawal within 12 months posttransplantation. In the CMV R(+) group, the QF-CMV assay yielded reactive results (QF-CMV[+]) in 51 of 67 patients (76%) compared with 7 of 19 patients (37%) in the CMV R(−) group (p = 0.001). In the CMV R(+) group, infection occurred in seven of 16 recipients (44%) who were QF-CMV(−) and eight of 51 recipients (16%) who were QF-CMV(+). In the CMV R(−) group, infection evolved in five of 12 recipients (42%) who were QF-CMV(−) and one of 7 recipients (14%) who were QF-CMV(+). No difference was found in the incidence of CMV infection stratified according to the QF-CMV results with regard to the recipients’ pretransplant CMV IgG serology (p = 0.985). Cytomegalovirus infection occurred in 15 of 36 patients (42%) with hypogammaglobulinemia (HGG) 90 days posttransplantation compared with two of 34 patients (6%) without HGG (p = 0.0004). Cytomegalovirus infection occurred in seven of 13 patients (54%) with lymphocytopenia compared with 14 of 70 patients (20%) without lymphocytopenia (p = 0.015). The multivariate analysis revealed that the nonreactive QuantiFERON-CMV assay was an independent risk factor for postprophylaxis CMV infection.ConclusionsIn kidney transplant recipients who received posttransplantation prophylaxis, negative QF-CMV results better defined the risk of CMV infection than initial CMV IgG status after prophylaxis withdrawal. Hypogammaglobulinemia and lymphocytopenia were risk factors for CMV infection.

Clinical experience with a novel assay measuring cytomegalovirus (CMV)-specific CD4+ and CD8+ T-cell immunity by flow cytometry and intracellular cytokine staining to predict clinically significant CMV events

“…A diagnostic test of immune competency against CMV can be utilized in different scenarios: at the end of primary prophylaxis, to determine if extended prophylaxis or close VL monitoring might be of benefit [10-16, 18, 22, 25]; at the end of treatment of CMV infection, to support the need for secondary prophylaxis [6,8]; finally, in patients with asymptomatic CMV DNAemia, to determine if antiviral treatment is truly indicated [12,13,17,23,29]. Herein, the CMV-TCIP performed well in a relatively small (but comparable in size to other similar studies [8,12,29,30]) case series, including all three potential scenaria.…”

“…Over the last decade, there has been growing interest in the development and bedside implementation of CMV-CMI assays. The Quantiferon®-CMV assay can predict late-onset CMV disease after primary prophylaxis [10][11][12][13][14][15][16] and spontaneous clearance of CMV DNAemia [12,13,29]; it has also been used in two interventional studies to guide primary [16] or secondary (after treatment for a CMV event) [8] prophylaxis. ELISPOT-based CMV-CMI assays (T-Track CMV® and T-SPOT®-CMV) can also help predict CMV events [17][18][19][20][21][22][23][24][25][26].…”

“…To this end, several CMV-specific assays evaluating cell-mediated immunity (CMI) have been developed: The Quantiferon®-CMV assay exposes whole blood to 21 CMV epitopes. Interferon gamma (IFN-γ) released from activated CD8+ T-cells is then quantified via ELISA, allowing for a measure of CMV-specific CD8+ (but not CD4+) T-cell response [8][9][10][11][12][13][14][15][16]. The T-Track CMV® and T-SPOT®-CMV assays first isolate peripheral blood mononuclear cells (PBMC), then expose them to a variety of CMV antigens or lysates; the resulting IFN-γ is quantified via ELISpot allowing for a measure of aggregate CMV-specific CD4+/CD8+ Tcell and NK-cell response, but not its individual components [17][18][19][20][21][22][23][24][25][26].…”

Assessment and prevention of cytomegalovirus infection in allogeneic hematopoietic stem cell transplant and in solid organ transplant: A multidisciplinary consensus conference by the Italian GITMO, SITO, and AMCLI societies

“…In the majority of SOT patients, IGRAs can be performed at any time before and not earlier than 30 days after the transplant. In SOT experiences, IGRAs were performed before transplant, after transplant before CMV infection, or after CMV infection (Table ) . Positive IGRAs, both before and after SOT, were variably predictive of a lower risk of CMV infection/disease, longer CMV‐free period, spontaneous viral clearance, lower rate of CMV infection recurrence, and lower level of CMV DNAemia.…”

An update on the treatment of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation

“…In recent years, numerous studies have assessed the role of T-cell immunological monitoring to determine the risk of CMV disease after solid organ and allo-HSCT. [31][32][33][34][35][36][37] In both settings, after documenting CMV-specific T-cell responses, observation in the wait of a spontaneous viral clearance, with no or only short term administration of any antiviral treatment, could be considered. However, if poor or absent CMVspecific T-cell responses are observed, more intensive viral monitoring and more aggressive antiviral prophylaxis or therapy strategies may be considered.…”