Utility of CMV-Specific Immune Monitoring for the Management of CMV in Solid Organ Transplant Recipients: A Clinical Update
Abstract
:1. Introduction: CMV and Its Burden on SOT
- Assessment of CMV T cell immunity prior to transplantation to predict risk of CMV infection post-transplantation;
- Assessment of CMV T cell immunity during or at the end of prophylaxis to predict risk of CMV infection;
- Assessment of CMV T cell immunity upon completing treatment of CMV infection to determine the need for secondary prophylaxis or predict risk of CMV relapse.
2. Host Immune Response to CMV
3. CMV-Specific T Cell Assays
3.1. Intracellular Cytokine Staining (ICS) and Flow Cytometry
3.2. Quantiferon-CMV (QFN-CMV)
3.3. CMV-ELISpot
4. Factors Impacting CMV-Specific T Cell Mediated Immunity
5. Clinical Utility of CMV Cell-Mediated Immunity (CMI) Assays
5.1. Can Pre-Transplant CMV CMI Predict Risk of CMV Disease Post-Transplant?
5.2. Can Assessment of CMV-CMI at the End of Anti-Viral Prophylaxis or Early after Transplantation Predict Risk of Subsequent CMV Disease?
5.3. Can Assessment of CMI at End of Treatment Determine Risk of Relapse?
6. Future Directions and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
Definitions
References
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ASSAYS | BRAND NAMES | CYTOKINES MEASURED | TARGET CELLS | ANTIGEN | ADVANTAGES | DISADVANTAGES |
---|---|---|---|---|---|---|
ELISPOT | T-SPOT.CMV T-TRACK.CMV | IFN-γ | CD4/CD8 | IE-1 and pp65 Peptides T-Activated CMV Proteins (IE-1, pp65) | Not Limited by HLA. Measures Both CD4/CD8 Response | Requires ELISpot Reader, No Standardization, Does Not Differentiate Between CD4 or CD8 Response |
ELISA | QuantiFERON-CMV | IFN-γ | CD8 | 21 Epitopes Mapped Within pp65, IE-1, pp50, IE-2, gB, and pp28; HLA Class I Restricted | Standardized, not Labor-Intensive | HLA Class I-Restricted, Sensitive to Lymphopenia, Measures CD8 Response Only |
FLOW CYTOMETRY | VIRACOR CMV T Cell Immunity Panel (TCIP) | IFN-γ CD69 | CD4/CD8 | CMV pp65 Peptide Mix or CMV Grade 2 Antigen Mix | Can Differentiate Between CD4 and CD8 Response; Potential to Measure a Variety of Cytokines and Cell Surface Markers | High Cost, No Standardization, Labor Intensive, Largely Limited to Research Use Only Except for VIRACOR TCIP |
CMV T Cell Assay | Author, Year, Location (Ref) | Organ, Donor/Recipient Status, No. Patients | Study Design and Primary Endpoint | Cutoff for Positive Test | Results | Limitations |
---|---|---|---|---|---|---|
QuantiFERON-CMV | Andreani et al., 2020, France [74] | Kidney, D+/R− N = 12 | Observational Study of Patients with Asymptomatic Viremia, Ability of CMI to Predict Spontaneous Viral Clearance or CMV Disease | >0.1 IU/mL | Spontaneous Clearance Occurred in 6/6 (100%) Patients with CMI at Time of Viremia vs. 1/5 (20%) with no CMI, p = 0.02 | Small Sample Size Observational Study, Single Organ |
QuantiFERON-CMV | Chiereghin et al., 2018, Italy [75] | Heart, D+/R− and R+, N = 44 | Retrospective, Utility of CMI to Predict CMV Infection in Preemptive vs. Prophylaxis Groups and to Predict Risk of Relapse After First Episode of CMV Infection | >0.2 IU/mL | In Prophylaxis Group, 66.7% with Indeterminate Result vs. 14.3% of Patients with CMI Developed CMV Infection, p = 0.036. No Difference in Pre-Emptive Therapy. No Patients who Developed CMI After Primary Infection Developed Relapse vs. 6/15 with Indeterminate or Negative Results, p = 0.032 | Retrospective Study, Heterogenous Donor/Recipient Serostatus, Single Organ |
QuantiFERON-CMV | Manuel et al., 2013, International [58] | All organs, D+/R−, N = 127) | Prospective Observational Study, Evaluation of CMI at End of Prophylaxis to Predict CMV Disease | >0.1 IU/mL | Patients with CMI at End of Prophylaxis Were Significantly Less Likely to Develop CMV Disease (6.4% vs. 22.2% vs. 58.3% for Positive vs. Negative vs. Indeterminate Result, p ≤ 0.001 | Observational Study Only |
QuantiFERON-CMV | Cantisan et al., 2013, Spain [61] | Lung, Kidney, R+ and R−, N = 55 | Evaluating Pre-Transplant CMI to Predict Post-Transplant CMV Replication (CMV Viremia, Asymptomatic and Disease) | >0.2 IU/mL | Pretransplant CMI Can Predict Development of CMV Independent of Serostatus | Small Number, Evaluated Asymptomatic Viremia |
QuantiFERON-CMV | Westall et al., 2019, Australia [76] | Lung, All, N = 118 | Interventional, Pilot, RCT; CMI Performed at End of Prophylaxis, Patients Randomized to CMI-Guided Prophylaxis vs. Standard of Care. Primary end Point CMV Detection by PCR in BAL | >0.2 IU/mL | CMI Guided Prophylaxis Had Lower Incidence of CMV Infection in Lung Allograft Than Standard of Care | Small Pilot Study, High Number of Indeterminate and Negative QFN-CMV Test Results, Endpoint Was BAL PCR Positivity |
QuantiFERON-CMV | Poglajen et al., 2020, Slovenia [77] | Heart, All, N = 154 | Prospective, Interventional Study, Non-Randomized Evaluating CMI-Guided Prophylaxis vs. Standard of Care, Primary End Point CMV Viremia and Disease | >0.2 IU/mL | CMI Guided Prophylaxis Resulted in Lower Rates of CMV Infection (5% vs. 19%, p = 0.03) but Longer Duration of Anti-Viral Prophylaxis Without any Increased Rates of Leukopenia | Non-Randomized Study, Single Center |
QuantiFERON-CMV | Kumar D et al., 2017, Canada [78] | All organs, All, N = 27 | Non-Randomized Interventional Study Evaluating Utility of CMI in Guiding Secondary Prophylaxis and at Predicting Risk of CMV Relapse | >0.2 IU/mL | At End of Therapy 9/13 Patients with Negative CMI vs. 1 of 14 Patients With Positive CMI at End of Therapy Developed CMV Recurrence (p = 0.001) | Small Sample Size, Non-Randomized Study |
QuantiFERON-CMV | Fernandez-Ruiz et al., 2020, Spain [79] | Kidney, R+ (N = 120) | Prospective, Observational (Non-Interventional) Study Evaluating CMI at End of Prophylaxis to Predict CMV Viremia and Disease in Patients that Received ATG Induction | >0.2 IU/mL | End of Prophylaxis CMI Did Not Predict CMV Infection | Non-Randomized Study, Non-Interventional. ATG Induction Only. |
T-Track CMV | Kim et al., 2020, Korea [80] | Kidney, R+, N = 133 | Observational Cohort Study Evaluating Pre-Transplant CMI to Predict Post-Transplant CMV Infection or Disease as Measured by CMV Antigen | >10 Spots per 200,000 Cells | Absence of Pre-Transplant CMI was Independent Risk Factor for CMV Infection, AHR 1.87 | Single Center, Observational, Using CMV Antigen |
T.SPOT.CMV | Jarque et al., 2020, Spain [69] | Kidney, R+, N = 160 | Prospective, Randomized, Multicenter, Observational Study Evaluating Whether Pre-Transplant CMI Could Predict Post-Transplant CMV Infection or Disease. Patients With and Without Pre-Transplant CMI Randomized to Either Pre-Emptive or Prophylactic Strategy | 20 Spots per 300,000 Cells | Patients With Negative Pre-Transplant CMI Had Higher Rates of Post-Transplant CMV Infection in Both Pre-Emptive (73.3% vs. 44.4%, OR 3.44) and Prophylaxis (33.3% vs. 4.1%, OR 11.75) Strategies. | |
ELISpot | Lucia et al., 2014, Spain [81] | Kidney, R+ and R−, N = 129 | Retrospective Case Control Study Evaluating Pre-Transplant CMI to Predict Post-Transplant CMV Infection | No a Priori Cutoff | Patients With High Pre-Transplant CMV-Specific T Cell Responses were Less Likely to Develop CMV Infection Post-Transplant | No a Priori Cutoff for ELISpot, Retrospective |
ELISpot | Schachtner et al., 2017, Germany [82] | Kidney, All, N = 326 | Prospective, Observational Trail Evaluating Pre-Transplant CMI to Predict Post-Transplant CMV Disease | No a Priori Cutoff | D+/R− and R+ With Evidence of Pre-Transplant CMI Did Not Have Lower Incidence of CMV Replication But Did Have Lower Peak CMV Viral Loads, Lower Incidence of CMV Disease, and were Less Likely to Require Anti-Viral Therapy | Single Center, Non-Interventional |
T.SPOT.CMV | Kumar et al., 2019, Multicenter [68] | Kidney, All, N = 583 | Prospective, Observational Study Evaluating Pre-Transplant CMI and End of Prophylaxis CMI to Predict CMV Infection | 40 Spots per 250,000 Cells | Patients With Positive CMI Either Pre-Transplant (NPV 95%) or at End of Prophylaxis (3% vs. 19.5%, p < 0.001, NPV > 97%) Were Less Likely to Develop CMV Infection | |
T.SPOT. CMV | Chanouzas et al., 2018, United Kingdom [83] | Kidney, All, N = 108 | Observational Cohort to Assess CMI at End of Prophylaxis to Predict CMV Viremia | IE1 (>25 Spots/2.5 × 10^5 PBMC’s) pp65 (>50 spots/2.5 × 10^5 PBMC’s) | Individuals With CMI at End of Prophylaxis were Less Likely to Develop CMV Viremia | Small Sample Size, Different Cutoff for Positivity than Other Studies, Observational Study |
T.SPOT.CMV | Jarque et al., 2018, Spain [84] | Kidney, R+, N = 96 | Observational Study to Assess CMI at End of Prophylaxis to Predict Subsequent CMV Infection | IE1 (>25 spots/3 × 10^5 PBMC’s) pp65 (>130 spots/3 × 10^5 PBMC’s) | CMV CMI Frequencies Were Significantly Lower in Patients Developing Late-Onset CMV (p < 0.001 or IE-1, p = 0.30 for pp65) | Single Center, Observational Study |
QuantiFERON-CMV CMV ELISpot | Lee et al., 2017, Korea [85] | Kidney, D+/R+ N = 124 | Assessment of Pre- and Post-Transplant CMI Using Two IGRAs to Determine Risk of Post-Transplant CMV | pp65 30 spots/200,000 cells IE-1 10 Spots/200,000 Cells | ELISpot at One-Month Post-Transplant Predicted Risk for Late-Onset CMV Infection. No Association Noted With QFN-CMV at Any Time Point. CMV ELISpot Pre-Transplant Could not Predict Post-Transplant CMV Infection. | Small Sample Size, Observational Cohort. Most Cases of CMV were Asymptomatic and Cleared Spontaneously |
T.SPOT.CMV | Donadeu et al., 2020, Spain [86] | Lung, R+ N = 60 | Retrospective Study Evaluating CMI at End of Prophylaxis to Predict Late Onset CMV Infection and Disease | 55 IE-1 Spots per 300,000 Cells | Lung Transplant Recipients With Late-Onset CMV had Significantly Lower CMI Compared to Those Who Did Not Have Late Onset CMV Infection (p = 0.045) | Retrospective, Small Sample Size, Non-Intervention |
ICS/Flow Cytometry | Singh et al. 2020, Multicenter [28] | Liver, D+/R−, N = 538 | RCT of D+/R− Liver Transplant Recipients Assigned to Prophylaxis vs. Pre-Emptive Therapy. As Secondary Outcome, Investigator Evaluated CMV-CMI | No Predefined Criteria | Patients Randomized to Pre-Emptive Therapy had Higher Frequency of CMV-Specific T Cells (Including Polyfunctional T Cell Responses) than Patients Randomized to Prophylaxis | Study Primarily Designed to Assess Clinical Outcome of CMV Infection Based on Prophylaxis vs. Pre-Emptive Treatment. |
ICS/Flow Cytometry | Snyder et al. 2016, USA [87] | Lung, D/R status unknown, N = 71 | Cross-Sectional Assessment of Polyfunctional CMI to Predict Protection from Subsequent CMV Infection | No Cutoff | Identified Several Polyfunctional T Cell Signatures That Predicted Protection from CMV Viremia | Small Sample Size, Single, Center, Observational Study, Samples Obtained at Variable Time Points After Transplant |
ICS/Flow Cytometry | Rogers, et al. 2020, USA [88] | All Transplant, All Donor-Recipient Status, N = 31 | Cross-Sectional Assessment of CMI in Patients with CMV Infection | 0.2% CMV-Specific CD4+ T Cells 0.2% CMV-Specific CD8+ T Cells | Patients with CMV-Specific CD4 T Cell Responses were Protected from Subsequent CMV Events with PPV of Protection from CMV Event of 85% | Cross-Sectional Analysis, Small Sample Size, Heterogeneous Population |
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Prakash, K.; Chandorkar, A.; Saharia, K.K. Utility of CMV-Specific Immune Monitoring for the Management of CMV in Solid Organ Transplant Recipients: A Clinical Update. Diagnostics 2021, 11, 875. https://doi.org/10.3390/diagnostics11050875
Prakash K, Chandorkar A, Saharia KK. Utility of CMV-Specific Immune Monitoring for the Management of CMV in Solid Organ Transplant Recipients: A Clinical Update. Diagnostics. 2021; 11(5):875. https://doi.org/10.3390/diagnostics11050875
Chicago/Turabian StylePrakash, Katya, Aditya Chandorkar, and Kapil K. Saharia. 2021. "Utility of CMV-Specific Immune Monitoring for the Management of CMV in Solid Organ Transplant Recipients: A Clinical Update" Diagnostics 11, no. 5: 875. https://doi.org/10.3390/diagnostics11050875