CMV-specific Cell-mediated Immunity Research Articles

Cytomegalovirus Infection After Solid Organ Transplantation: How I Use Cell-Mediated Immune Assays for Management

Introduction: The pathogenesis and outcome of cytomegalovirus (CMV) infection after solid organ transplantation (SOT) reflects the interplay between viral replication and CMV-specific immunity. Despite advances in its diagnosis and treatment, CMV continues to cause significant morbidity after SOT. Since CMV is an opportunistic pathogen that occurs as a result of impaired pathogen-specific immunity, laboratory assays that measure CMV-specific immune responses may be useful in assisting clinicians in its management. Methods and Results: The author summarizes the evolving and emerging data on the clinical utility of assays that quantify cell-mediated immune responses to CMV in SOT recipients. The majority of publications are observational studies that demonstrate that a lack or deficiency in CMV-specific cell-mediated immunity is correlated with a heightened risk of primary, reactivation, or recurrent CMV after transplantation. A few prospective interventional studies have utilized CMV-specific cell-mediated immune assays in guiding the duration of antiviral prophylaxis among CMV-seropositive SOT recipients. Likewise, CMV-specific cell-mediated immunity assays have been suggested to inform the need for secondary antiviral prophylaxis and immunologic optimization to prevent CMV relapse after treatment. Conclusions: CMV-specific cell-mediated immune assays are emerging to assist transplant clinicians in predicting a patient’s risk of CMV after transplantation, and these assays have been utilized to individualize the approach to CMV prevention and treatment. The author suggests the conduct of more interventional studies to further solidify the role of CMV-specific cell-mediated immune assays in routine clinical practice.

The adaptive and innate immune systems coordinate for successful control of CMV infection

Previous studies of the immune control of cytomegalovirus infection have primarily focused on analysis of the traditional adaptive T-cell response. Donadeu etal. bring a new perspective through evaluation of multiple adaptive and innate immune subtypes in parallel with cytomegalovirus-specific cell-mediated immunity in a prospective cohort of kidney transplant recipients with findings validated in 2 independent studies. Identification of a natural killer T-cell subtype associated with cell-mediated immunity and freedom from cytomegalovirus infection demonstrates the importance of the coordinated innate and adaptive immune response for effective viral control.

Prevention of Cytomegalovirus Infection in Solid Organ Transplant Recipients: Guidelines by the Korean Society of Infectious Diseases and the Korean Society for Transplantation.

Cytomegalovirus (CMV) is the most important opportunistic viral pathogen in solid organ transplant (SOT) recipients. The Korean guideline for the prevention of CMV infection in SOT recipients was developed jointly by the Korean Society for Infectious Diseases and the Korean Society of Transplantation. CMV serostatus of both donors and recipients should be screened before transplantation to best assess the risk of CMV infection after SOT. Seronegative recipients receiving organs from seropositive donors face the highest risk, followed by seropositive recipients. Either antiviral prophylaxis or preemptive therapy can be used to prevent CMV infection. While both strategies have been demonstrated to prevent CMV infection post-transplant, each has its own advantages and disadvantages. CMV serostatus, transplant organ, other risk factors, and practical issues should be considered for the selection of preventive measures. There is no universal viral load threshold to guide treatment in preemptive therapy. Each institution should define and validate its own threshold. Valganciclovir is the favored agent for both prophylaxis and preemptive therapy. The evaluation of CMV-specific cell-mediated immunity and the monitoring of viral load kinetics are gaining interest, but there was insufficient evidence to issue recommendations. Specific considerations on pediatric transplant recipients are included.

Cytomegalovirus (CMV) Reactivation and CMV-Specific Cell-Mediated Immunity After Chimeric Antigen Receptor T-Cell Therapy.

The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor-modified T-cell immunotherapy (CARTx) is poorly understood owing to a lack of routine surveillance. We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx recipients and tested plasma samples for CMV before and weekly up to 12 weeks after CARTx. We assessed CMV-specific cell-mediated immunity (CMV-CMI) before and 2 and 4 weeks after CARTx, using an interferon γ release assay to quantify T-cell responses to IE-1 and pp65. We tested pre-CARTx samples to calculate a risk score for cytopenias and infection (CAR-HEMATOTOX). We used Cox regression to evaluate CMV risk factors and evaluated the predictive performance of CMV-CMI for CMV reactivation in receiver operator characteristic curves. CMV was detected in 1 patient (1.4%) before and in 18 (25%) after CARTx, for a cumulative incidence of 27% (95% confidence interval, 16.8-38.2). The median CMV viral load (interquartile range) was 127 (interquartile range, 61-276) IU/mL, with no end-organ disease observed; 5 patients received preemptive therapy based on clinical results. CMV-CMI values reached a nadir 2 weeks after infusion and recovered to baseline levels by week 4. In adjusted models, BCMA-CARTx (vs CD19/CD20) and corticosteroid use for >3 days were significantly associated with CMV reactivation, and possible associations were detected for lower week 2 CMV-CMI and more prior antitumor regimens. The cumulative incidence of CMV reactivation almost doubled when stratified by BCMA-CARTx target and use of corticosteroids for >3 days (46% and 49%, respectively). CMV testing could be considered between 2 and 6 weeks in high-risk CARTx recipients.

Evaluation of the fully automated LIAISON®XL chemiluminescence analyzer for QuantiFERON®-CMV testing in transplant recipients.

Monitoring CMV-specific cell-mediated immunity by the QuantiFERON®-CMV (QF-CMV) may be useful in predicting the risk of CMV infection in transplant recipients (TR). As the QuantiFERON-Tuberculosis (QFT®-Plus) became available on the fully automated LIAISON®XL chemiluminescence (CLIA) analyzer, we evaluated the performance of the QF-CMV on the LIAISON®XL analyzer using the QuantiFERON®-TB Gold Plus reagent. Between 2018 and 2022, 81 samples from TR were collected at the Department of Virology of Limoges Hospital, France. Whole blood was collected into each of the three QF-CMV collection tubes: a CMV-antigen tube (QF-Ag), a mitogen tube (QF-Mg) (positive control), and a nil tube (negative control). The QF-CMV was performed on the LIAISON®XL analyzer, and results were compared with those obtained by conventional microplate ELISA. Intra- and inter-assay coefficients of variation were inferior to 20%. No inter-sample contamination was found (p=0.366). The level of concordance between CLIA and the commonly used ELISA method was 88.9%. Positive and negative percent agreements were 92.3% and 85.7%, respectively, with a very good agreement between assays (κ=0.818). Most discordances were due to indeterminate- or negative-ELISA/positive-CLIA results (most of ELISA results were borderline). Linear regression analyses demonstrated a strong correlation between both assays (QF-Ag Pearson's r=0.978, QF-Mg Pearson's r=0.963). No significant difference was observed in median QF-CMV values between both assays (QF-Ag p=0.776; QF-Mg p=0.853; Mann-Whitney U test). The Bland-Altman plots showed a minor difference in IFN-γ release (QF-Ag -0.069 IU/ml, 95% limits of agreement (LoA): -1.589; 1.451; QF-Mg0.190IU/ml, 95% LoA: -2.070; 2.450). Automated QF-CMV with CLIA is comparable to QF-CMV performed by ELISA with a presumably higher sensitivity for IFN-γ detection that may result in the conversion of samples close to the ELISA cut-off into positive results. Moreover, the use of a random-access analyzer allows to optimize the follow-up of TR.

The effect of late-onset CMV infection on the outcome of renal allograft considering initial graft function.

Delayed graft function (DGF) increases the renal allograft failure risk. Late-onset Cytomegalovirus (CMV) infection's effect on the association between DGF and allograft failure has not been determined. In this retrospective cohort, we included all renal allograft recipients at London Health Sciences Centre from January 1, 2014 to December 30, 2017, and continued clinical follow-up until February 28, 2020. We determined whether late-onset CMV infection affects the association between DGF and allograft failure in stratified and Cox proportional hazard analyses. Of 384 patients (median age [interquartile range]: 55 [43.3-63]; 38.7% female), 57 recipients (14.8%) were diagnosed with DGF. Patients with DGF were at a greater risk of CMV infection than patients without DGF (22.8% vs. 11.3%, p = .017). Late-onset CMV infection (odds ratio [OR]: 4.7, 95% CI: 2.07-10.68) and rejection (OR: 9.59, 95% CI: 4.15-22.16) significantly increased the risk of allograft failure in recipients with DGF. Patients with DGF had a significantly greater risk of graft failure than those without DGF (17.5% vs. 6.1%, p = .007). In the adjusted Cox hazard model, CMV infection significantly increased the risk of allograft failure (aHR: 3.19, 95% CI: 1.49-6.84). Late-onset CMV infection considerably increased the risk of graft failure in patients with DGF. A hybrid preventive model including prophylaxis followed by CMV-specific cell-mediated immunity monitoring may decrease the risk of allograft failure in recipients with DGF.

The influence of HLA A, B, C, DR alleles and HLA haplotypes on cytomegalovirus-specific cell mediated immunity in seropositive Korean kidney transplant candidates.

We evaluated the effect of specific HLA alleles and haplotypes on cytomegalovirus (CMV)-specific cell mediated immunity (CMI) in kidney transplant (KT) candidates. CMV-specific ELISPOT against pp65 and IE-1 antigens (hereafter referred to as pp65 and IE-1, respectively) was performed in 229 seropositive KT candidates. We analyzed the results related to 44 selected HLA alleles (9 HLA-A, 15 HLA-B, 9 HLA-C, and 11 HLA-DR) and 13 HLA haplotypes commonly found in study participants. The pp65 and IE-1 results in 229 seropositive candidates were 227.5 (114.5-471.5) and 41.0 (8.8-185.8) (median [interquartile range]) spots/2 × 105 PBMCs, respectively. The pp65 and IE-1 results showed significant differences between candidates with different HLA alleles (A*02 vs. A*26 [p = 0.016], A*24 vs. A*30 [p = 0.031], B*07 vs. B*46 [p = 0.005], B*54 vs. B*35 [p = 0.041], B*54 vs. B*44 [p = 0.018], B*54 vs. B*51 [p = 0.025], and C*06 vs. C*14 [p = 0.034]). HLA-A*02 and B*54 were associated with increased pp65 and IE-1 results, respectively (p = 0.005 and p < 0.001, respectively). In contrast, the HLA-A*26 and B*46 alleles were associated with a decreased pp65 response, whereas the A*30 allele was associated with a decreased IE-1 response (p < 0.05). The pp65 results correlated with the HLA-A allele frequencies (R = 0.7546, p = 0.019) and the IE-1 results correlated with the HLA-C allele frequencies of the study participants (R = 0.7882, p = 0.012). Among 13 haplotypes, HLA-A*30 ~ B*13 ~ C*06 ~ DRB1*07 showed decreased CMV-CMIs compared to the other HLA haplotypes, probably due to a combination of HLA alleles associated with lower CMV-CMIs. Our results demonstrated that CMV-specific CMIs may be influenced by the HLA allele as well as the HLA haplotype. To better predict CMV reactivation, it is important to estimate risk in the context of HLA allele and haplotype information.

Comparison of intracellular cytokine staining versus an ELISA-based assay to assess CMV-specific cell-mediated immunity in high-risk kidney transplant recipients.

The best method for monitoring cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) among high-risk kidney transplant (KT) recipients remains uncertain. We assessed CMV-CMI by intracellular cytokine staining (ICS) by flow cytometry and a commercial interferon (IFN)-γ release assay (QuantiFERON®-CMV [QTF-CMV]) at posttransplant months 3, 4, and 5 in 53 CMV-seropositive KT recipients that had received induction therapy with antithymocyte globulin (ATG) and a 3-month course of valganciclovir prophylaxis. The discriminative capacity (areas under receiver operating characteristics curve [auROCs]) and diagnostic accuracy to predict immune protection against CMV infection from the discontinuation of prophylaxis to month 12 were compared between both methods. There was significant although moderate correlations between CMV-specific IFN-γ-producing CD8+ T-cell counts enumerated by ICS and IFN-γ levels by QTF-CMV at months 3 (rho: 0.493; p = 0.005) and 4 (rho: 0.440; p = 0.077). The auROCs for CMV-specific CD4+ and CD8+ T-cells by ICS were nonsignificantly higher than that of QTF-CMV (0.696 and 0.733 vs. 0.678; p = 0.900 and 0.692, respectively). The optimal cut-off of ≥0.395 CMV-specific CD8+ T-cells yielded a sensitivity of 86.4%, specificity of 54.6%, positive predictive value of 79.2% and negative predictive value of 66.7% to predict protection. The corresponding estimates for QTF-CMV (IFN-γ levels ≥0.2 IU/mL) were 78.9%, 37.5%, 75.0%, and 42.9%, respectively. The enumeration of CMV-specific IFN-γ-producing CD8+ T-cells at the time of cessation of prophylaxis performed slightly better than the QTF-CMV assay to predict immune protection in seropositive KT recipients previously treated with ATG.

Role of cytomegalovirus specific cell-mediated immunity in the monitoring of cytomegalovirus infection among living donor liver transplantation adult recipients: A single-center experience.

Cytomegalovirus (CMV) is one of the most common post-transplant viral infections causing significant morbidity and occasional mortality. Limited literature on the potential role of pre-transplant CMV-specific cell-mediated immunity (CMV-CMI) is available. This study aimed to evaluate the clinical utility of pre-transplant CMV-CMI monitoring in the occurrence of post-transplant CMV infection. This was a prospective, observational study where all adult CMV seropositive patients undergoing living donor liver transplantation at a tertiary care institute were enrolled. CMV-CMI was measured using QuantiFERON-CMV (Qiagen GmbH, Hilden, Germany) and interpreted as positive if the value was ≥0.2 IU/ml, 1-2 days prior to the transplant. Based on pre-transplant CMV-CMI, cases were classified into Group 1 (n=13, 43.3%) (positive) and Group 2 (n=17, 56.7%) (negative). CMV infection was defined as the detection of CMV-DNA > 2.7 log10 IU/ml in plasma specimens. The mean age was 43 years with male (n=29, 96.9%) predominance. Overall 40% of recipients developed post-transplant CMV infection, two (15.4%) in group 1 and 10 (58.8%) in group 2 (p-value=0.016). Recipients in group 2 had 87% higher odds (odds ratio 0.13, confidence interval [CI] 95) of developing post-transplant CMV infection compared to group 1. The overall median duration of occurrence of post-transplant CMV infection was 26 days with the median viral load being 2.8 log10 IU/ml. The treatment duration was 13 days in group 1 and 28 days in group 2 (p=0.003). Group 1 recipients showed rapid clearance of CMV-DNA within 7 days compared to group 2 in which it was 21 days (p=0.004, CI 95). Pre-transplant CMV-CMI may play a protective role against post-transplant CMV infection and can serve as an adjunct for pre-transplant risk stratification.

Cytomegalovirus Specific Cell-Mediated Immunity Status in Women with Preeclampsia: A Case-Control Study.

Preeclampsia, a pregnancy-specific complication, has been associated with cytomegalovirus (CMV) infection in observational studies. CMV-specific T cell response plays a major role in viremia clearance. We explored whether CMV-specific cell-mediated immunity (CMI) status is associated with preeclampsia in pregnant women. CMV-specific CMI was assessed using CMV-QuantiFERON (QF-CMV) assay in plasma serum of 35 women with preeclampsia as well as 35 normal pregnant controls, retrospectively. Participants were matched for gestational age in a 1:1 ratio. The proportion of reactive results, the mean value of interferon-gamma (IFN-γ) level produced in mitogen and antigen tubes were compared between the cases and controls through Chi-square and Wilcoxon rank-sum tests, respectively. The odds ratio and confidence interval were calculated as well. No significant differences observed between demographic characteristics of the case and control groups. The QF-CMV assay turned reactive (QF-CMV [ + ]) Women with preeclampsia had lower mean IFN-γ levels in antigen tube compared with normal pregnant controls. There were no statistically significant differences in the value of mitogen tube between case and controls women with suppressed CMV-CMI were 6.3 times more likely to have preeclampsia. This result even strengthened after adjustment for age, gestational age, and gravidity. Our findings support an association between suppressed CMV-specific CMI and preeclampsia.

1587. Clinical Utility of a Cytomegalovirus (CMV)-specific T Cell Assay in Assessing the Risk of Post-Prophylaxis CMV Infection and Post-Treatment Relapse

Abstract Background Cytomegalovirus (CMV) causes significant morbidity in solid organ transplant recipients (SOTR). As a lack of immunity predisposes to infection, a laboratory test that measures CMV-specific cell-mediated immunity (CMV CMI) may help guide antiviral prophylaxis, predict relapses and correlate with outcomes. We assessed CMV CMI in CMV D+/R- patients during valganciclovir primary prophylaxis and in CMV viremic SOTRs during antiviral treatment, and correlated the results with post-prophylaxis CMV infection and post-treatment relapse, respectively. Methods CMV CMI was assessed in two groups of SOTRs using the QuantiFERON© CMV interferon-gamma release assay (IGRA), with level &amp;gt;0.2 IU/mL suggestive of immunity. The first group included CMV D+/R- SOTRs who underwent monthly CMV CMI testing during 6 months of valganciclovir prophylaxis. These patients were prospectively followed for CMV episodes for 1 year post transplant. The second group included SOTRs with CMV viremia or disease, who underwent CMV CMI testing at time of CMV diagnosis and at various time points during antiviral treatment. These patients were prospectively followed for CMV relapse for 1 year post-primary CMV episode. Standard definitions were used to define CMV infection and disease. Results In the primary prophylaxis cohort, 24 CMV mismatched (D+/R-) SOTRs were enrolled. Only 1 patient (4.2%) demonstrated a CMV CMI &amp;gt;0.2 IU/mL by the end of prophylaxis; this patient did not develop CMV disease. Four (16.6%) patients developed post-prophylaxis CMV infection, none of which had CMV CMI &amp;gt;0.2 IU/ml. In the post-treatment cohort, 20 CMV viremic SOTRs were enrolled, including 12 D+/R- (60%). Eighteen (90%) had CMV CMI levels &amp;gt;0.2 IU/mL by end of treatment and none developed CMV relapse. In contrast, the single patient who relapsed after treatment had a CMV CMI response &amp;lt; 0.2 IU/ml (p=0.05). Conclusion CMV D+/R- SOTRs are unlikely to develop CMV CMI during valganciclovir prophylaxis. Thus, the utility of CMV CMI for risk stratification of post-prophylaxis CMV infection in CMV D+/R- SOTRs is questionable. Conversely, CMV CMI testing may potentially be a useful marker of CMV relapse risk after treatment and guide the role of secondary antiviral prophylaxis. Disclosures Elitza Theel, PhD, D(ABMM), Euroimmun US: Advisor/Consultant|Oxford Immunotech: Advisor/Consultant|Roche Diagnostics: Advisor/Consultant|Serimmune Inc: Advisor/Consultant Raymund R. Razonable, MD, American Society of Transplantation: Board Member|gilead: Grant/Research Support|novartis: DSMB|regeneron: Grant/Research Support|Roche: Grant/Research Support.

Seasonal variation of cytomegalovirus disease in kidney transplant recipients.

Studies conducted in the northern United States found cytomegalovirus (CMV) disease after liver transplantation follows a seasonal pattern, with increased incidence in fall and winter. This has not been evaluated in kidney transplant recipients. Improved understanding of CMV seasonality may help guide use of preventative therapies. We evaluated adult patients receiving a kidney transplant at our center in Wisconsin from January 1, 1995 to December 31, 2018. CMV event was defined as quantifiable viral replication with clinical signs or symptoms suspicious for CMV per current consensus recommendations. Seasons were divided as follows: winter (December-February), spring (March-May), summer (June-August), and fall (September-November). The primary objective was to evaluate the annual distribution of CMV disease and determine whether this differed by season. There were 6151 kidney transplants in the study period. A total of 913 patients had 1492 episodes of CMV. Median time from transplant to first detection was 5.51 months (interquartile range [IQR] 2.87-11.7). The observed overall incidence exceeded the expected incidence in winter (+.7%), spring (+5.5%), and fall (+3.4%) and was less than expected in summer (-9.5%) (p=.18). The incidence of CMV during summer, however, was 21% less than expected (p=.001) in recipients who were CMV positive (R+) at the time of transplantation. No such difference was observed in CMV negative recipients (R-; p=.58). CMV after kidney transplant appears to be less common during the summer season in patients who were R+ at transplant but does not follow seasonal variation in R-. Reasons for this are unclear but are likely related to CMV-specific cell-mediated immunity. These findings may have clinical implications, particularly the use of non-pharmacologic strategies to improve response to antiviral therapy.

Analysis of HLA types with cytomegalovirus-specific cell mediated immunity in seropositive kidney transplant candidates

Analysis of HLA types with cytomegalovirus-specific cell mediated immunity in seropositive kidney transplant candidates

Cytomegalovirus antiviral stewardship in solid organ transplant recipients: A new gold standard.

Antimicrobial stewardship programs (ASPs) are essential entities that promote the appropriate use of antimicrobials, leading to improved patient outcomes and reduced resistance. Application to the immunocompromised host is a natural progression for expansion. Cytomegalovirus (CMV) infection is a common complication following solid organ transplant with significant implications on graft survival, making it an attractive ASP target. The aim of this piece is to review our center-specific experience with the development, implementation, and maintenance of a CMV stewardship initiative at a large transplant center. Our CMV stewardship initiative began in 2018. Herein, we review 3 years' experience and quality-related improvement that occurred from initiation to present state and share our stewardship algorithms. Special attention is paid to the impact of the program as well as our increased understanding of the complex interplay between prevention, treatment, and host development of CMV-specific cell-mediated immunity (CMI). We found our stewardship initiative not only reduced the incidence of ganciclovir resistance but also streamlined care via a centralized and structured approach. This objective, protocolized program has resulted in a significant shift away from a reactive to a proactive state and in turn, reduced CMV treatment rates (26% at initiation to 12% in the current state, p=.012). A dedicated multidisciplinary team focused on CMV stewardship is imperative in providing a patient-centered approach focused on development of CMV-specific CMI, and as a result prevention of CMV disease. We believe these programs will be the new gold standard for CMV management.

424.4: The Protection From CMV Infection in Solid Organ Transplants Is Highly Dependent on CMV T-Cell Specific Immunity And Type of Organ Transplant

Introduction: The CMV specific immune recovery is known to control viral infection and disease. The CMV specific cell-mediated immunity (CMI) and CMV specific humoral immune response (IgG titer and IgG avidity) was explored as candidate biomarker predictive of CMV infection. Methods: 653 observations from 297 SOT including 103 kidney (K), 60 liver (L), 47 heart (H), 87 Lung (Lu) transplants. The follow-up was 0-400 days after transplant. The following parameters were examined: 1) CMV serostatus before transplant 2) CMV IgG titer 3) CMV IgG avidity 4) CMV-ELISPOT 5) primary (D+/R-) or non-primary (D±/R+) CMV infection 6) CMV viremia. Data were statistically analyzed using ANOVA and linear regression analysis and spline model. Results: The main findings of the study are: 1) CMV IgG titers and avidity are not predictive biomarker for CMV infection. The CMV IgG titer and IgG avidity levels are comparable either in infected and non-infected patients. 2) CMV viral load is statistically different between infected D±/R+ and D+/R. The viral load in infected D+/R- is 1 Log higher compared to D±/R+ (10^5 vs 10^4 respectively) 4) The CMV immune reconstitution is more rapid and efficient in D±/R+ compared to D+/R- 5) D±/R+ and D+/R- Kidney and Lung transplants display a statistically significant lower CMI compared to heart and liver transplants; 6) Kidney and Lung transplants display a similar pattern of immune recovery 7) The CMV cell mediated immunity biomarker is predictive of infection in all organs with exception of lung transplants. Conclusions: The study shows a marginal role of humoral immunity in controlling CMV infection. The pattern of CMI immune recovery is highly dependent upon pre-transplant CMV serostatus, type of organ transplant and immunosuppression therapy. High levels of CMV specific cell-mediated immunity correlate with a reduced CMV infection risk in heart, kidney and liver transplants. A different scenario emerged in lung transplants: high levels of circulating CMV specific T-cells can be found in lung transplants but cannot prevent CMV infection and clear the virus. In this view the lung may be considered a “sanctuary site” for CMV replication.

Humoral/Cellular Immune Discordance in Stem Cell Donors: Impact on Cytomegalovirus-Specific Immune Reconstitution after Related Hematopoietic Transplantation

Cytomegalovirus (CMV) reactivation is an important cause of complications after hematopoietic stem cell transplantation (HSCT). Discrepancies between serologic and cellular CMV-specific immune response have been reported. This study evaluated the impact of lack of CMV-specific CD8+ T cell response in seropositive donors (ie, discordant donors) on the reconstitution of CMV-specific cell-mediated immunity (CMI) after related HSCT in seropositive recipients. CMV-CMI was assessed in donors and recipients using the QuantiFERON-CMV assay (QF). CMV-CMI was prospectively assessed for 1 year in 81 CMV-seropositive HSCT recipients with a haploidentical or matched related donor. A Cox proportional hazard regression analysis was performed. Of the 67 CMV-seropositive donors, 54 (80.6%) were D+QFpos. The remaining 13 CMV-seropositive donors (19.4%) had a QFneg result and thus were classified as discordant donors (D+QFneg). We found that patients with D+QFneg had a significantly higher risk of impaired CMV-CMI reconstitution compared with patients with D+QFpos (log-rank test, P=.001) or D- donors (log-rank test, P = .023). In addition, the D+QFneg group had a higher incidence of single-episode reactivation compared with D+QFpos or D- donors (69.2% versus 44.4% and 28.6%, respectively) but a lower incidence of CMV recurrence compared with the D- group (7.7% versus 57.1%; P=.003). After adjusting for other relevant variables, immune discordance in donors was independently associated with impaired CMV-CMI reconstitution compared with D+QFpos donors (adjusted hazard ratio [HR], 0.18; 95% confidence interval [CI], .06 to .52; P=.001) and D- donors (adjusted HR, .17; 95% CI, .05 to .59; P=.005). Discordant donors were associated with undetectable CMV-CMI during the 12-month follow-up period using the QF assay. The inability of these patients to become QFpos persisted even after CMV reactivation. This might be related to the low frequency of CMV recurrence in this group. CMV-CMI assessment, in conjunction with CMV serostatus, can be of utility to better classify stem cell donors as well as the risk of impaired CMV-CMI reconstitution after HSCT.

Laboratory diagnostic testing for cytomegalovirus infection in solid organ transplant patients.

Human cytomegalovirus (CMV) infection, which is one of the most common complications in transplant recipients, increases the risk of graft loss and rejection. Laboratory strategies for diagnosing CMV infection rely on the measurement of viral DNAemia and CMV-specific cell-mediated immunity (CMV-CMI). The CMV quantitative nucleic acid amplification test (QNAT) enabled the spread of preemptive therapy and prompted recommendations for surveillance, diagnosis, and monitoring. Despite the implementation of the World Health Organization international standard for calibration, variability of QNAT persists due to technical issues. CMV immunoglobulin G serology is the standard method for CMV immune screening of transplant candidates and donors. Assays for CMV-CMI play an important role in helping to predict the risk and to develop an individualized CMV management plan. Genotypic testing for resistance is needed when drug-resistant CMV infection is suspected. Here, we review the state of the art of laboratory tests for CMV infection in solid organ transplantation.

Immunoguided Discontinuation of Prophylaxis for Cytomegalovirus Disease in Kidney Transplant Recipients Treated With Antithymocyte Globulin: A Randomized Clinical Trial.

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. Our aim was to determine whether it is effective and safe to discontinue prophylaxis when CMV-CMI is detected and to continue with preemptive therapy. In this open-label, noninferiority clinical trial, patients were randomized 1:1 to follow an immunoguided strategy, receiving prophylaxis 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 2 deleterious events (CMV disease/replication and neutropenia). 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 = .149) and replication (17.1% vs 13.5%; log-rank test, P = .422) between both arms. Incidence of neutropenia was lower in the immunoguided arm (9.2% vs 37.8%; odds ratio, 6.0; P < .001). A total of 66.1% of patients in the immunoguided arm showed a better DOOR, indicating a greater likelihood of a better outcome. 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. NCT03123627.

A Prospective Study of Cytomegalovirus-Specific Cell-Mediated Immune Monitoring and Cytomegalovirus Infection in Patients With Active Systemic Lupus Erythematosus Receiving Immunosuppressants.

BackgroundThe effects of cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) on CMV infection in patients with autoimmune diseases receiving immunosuppressants have not been explored.MethodsPatients with active systemic lupus erythematosus (SLE) were preemptively monitored for clinically significant CMV infection (CsCMVI; defined as plasma CMV DNA loads >3 log10 IU/mL). CMV-specific CMI was assessed using an enzyme-linked immunosorbent assay (QuantiFERON-CMV [QF]) before as well as 1 and 3 months after intense immunosuppressive therapy.ResultsThe study included 55 patients with active SLE; patients were a mean age (SD) of 34 (13) years and had a median SLE Disease Activity Index 2000 score (SD) of 14 (8), and 93% were female. Most patients had renal involvement (67%), received methylprednisolone (93%), and were CMV-seropositive (95%). Thirteen (23.6%) patients developed CsCMVI. Among patients with active SLE who were QF-negative (QF–) and QF-positive (QF+) before receiving immunosuppressive therapy, 28.6% and 25% developed CsCMVI, respectively (P = .69). However, 1 month postimmunosuppression, more QF– than QF+ patients developed CsCMVI (44.4% vs 11.8%; P = .03; adjusted hazard ratio, 4.97; 95% CI, 1.07–23.10; P = .04).ConclusionsPatients with active SLE and low CMV-specific T-cell responses could develop CMV infection after receiving immunosuppressants. Further studies should focus on CMV-specific CMI among patients with autoimmune diseases.

Utility of CMV-Specific Immune Monitoring for the Management of CMV in Solid Organ Transplant Recipients: A Clinical Update.

Cytomegalovirus (CMV) is one of the most important opportunistic infections in solid organ transplant (SOT) recipients. However, current techniques used to predict risk for CMV infection fall short. CMV-specific cell mediated immunity (CMI) plays an important role in protecting against CMV infection. There is evidence that assays measuring CMV-CMI might better identify SOT recipients at risk of complications from CMV compared to anti-CMV IgG, which is our current standard of care. Here, we review recently published studies that utilize CMV-CMI, at various points before and after transplantation, to help predict risk and guide the management of CMV infection following organ transplantation. The evidence supports the use of these novel assays to help identify SOT recipients at increased risk and highlights the need for larger prospective trials evaluating these modalities in this high-risk population.