Ann Clin Microbiol.  2021 Jun;24(2):31-43. 10.5145/ACM.2021.24.2.1.

Safety and Effectiveness of Cytomegalovirus Specific Antigen Induced Interferon-Gamma ELISPOT/ELISA: A Systematic Review

• Choi W
• Hahn J
• Lee W
• Shin C

• KMID: 2516726
• DOI: http://doi.org/10.5145/ACM.2021.24.2.1

Abstract

Background
This study evaluated the safety and effectiveness of the cytomegalovirus (CMV) Specific Antigen Induced Interferon-Gamma ELISPOT (enzyme-linked immunosorbent spot)/ELISA (enzyme-linked immunosorbent assay) procedure in predicting the risk of CMV infection/disease in immunocompromised patients through a systematic literature review.
Methods
The searched electronic databases included MEDLINE, EMBASE and the Cochrane Library. A total of 884 non-duplicate citations were retrieved and a total of 25 studies (15 cohort studies, 10 cross-sectional studies) were included in this review. Study subjects were selected among patients with solid organ, hematopoietic stem cell transplantation, or those who were on hemodialysis. Data extraction and literature quality assessment were carried out independently by two researchers.
Results
Most of the studies were conducted on patients with solid organ transplants. As it is conducted outside the body, CMV Specific Antigen Induced Interferon-Gamma ELISPOT/ELISA assay was safe. Regarding its effectiveness, most studies on risk analysis based on prognosisrelated outcomes reported that the inactive group showed a significantly higher hazard ratio or odds ratio than the active group. Results of Kaplan-Meier survival analysis also showed that the inactive group had a significantly higher incidence of CMV event (CMV infection, CMV disease, other events) than the active group. However, various thresholds for CMV cell immune response were reported, as was a broad range of predictive diagnostic accuracies.
Conclusion
CMV Specific Antigen Induced Interferon-Gamma ELISPOT/ELISA assay has potential to stratify the risk of CMV infection/disease among solid organ transplant patients and to determine a policy for a prophylaxis/preemptive. However, additional literature evidence is needed to establish thresholds for CMV cell immune response and standardized tests.

Keyword

CMV-Specific Antigen-Induced Interferon Gamma; Effectiveness; Enzyme-linked immunosorbent assay; Enzyme-linked immunospot assay; Safety

Figure

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  Fig. 1. Flow chart of literature selection process.ELISPOT, enzyme-linked immunospot; ELISA, enzyme-linked immunosorbent assay.

Reference

1. Deborska-Materkowska D, Perkowska-Ptasinska A, Sadowska A, Gozdowska J, Ciszek M, Serwanska-Swietek M, et al. Diagnostic utility of monitoring cytomegalovirus-specific immunity by QuantiFERON-cytomegalovirus assay in kidney transplant recipients. BMC Infect Dis 2018;18:179.

2. Yang CW, Kim YO, Kim YS, Kim SY, Moon IS, Ahn HJ, et al. Clinical course of cytomegalovirus (CMV) viremia with and without ganciclovir treatment in CMV-seropositive kidney transplant recipients. Longitudinal follow-up of CMV pp65 antigenemia assay. Am J Nephrol 1998;18:373-8.

3. Ki HK, Kim CK, Kim SW, Lee H, Kim S, Peck KR, et al. Cytomegalovirus infections after renal transplantation. Korean J Infect Dis 1999;31:341-5.

4. Ki HK, Sohn KM, Rhee JY, Wi YM, Moon CS, Oh WS, et al. Usefulness of cytomegalovirus(CMV) antigenemia assay after liver trasnplantation. Infect Chemother 2005;37:199-207.

5. Jameson JL, Fauci A, et al. eds. Harrison's principles of internal medicine, 20th ed. New York; McGraw-Hill, 2017:Vol.1 & Vol.2.

6. Rittà M, Costa C, Sidoti F, Ballocco C, Ranghino A, Messina M, et al. Pre-transplant assessment of CMV-specific immune response by Elispot assay in kidney transplant recipients. New Microbiol 2015;38:329-35.

7. Kim SH, Lee HJ, Kim SM, Jung JH, Shin S, Kim YH, et al. Diagnostic usefulness of cytomegalovirus (CMV)-specific T cell immunity in predicting CMV infection after kidney transplantation: a pilot proof-of-concept study. Infect Chemother 2015;47:105-10.

8. Abate D, Cesaro S, Cofano S, Fiscon M, Saldan A, Varotto S, et al. Diagnostic utility of human cytomegalovirus-specific T-cell response monitoring in predicting viremia in pediatric allogeneic stem-cell transplant patients. Transplantation 2012;93:536-42.

9. Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L, et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2013;96:333-60.

10. Healthcare improvement scotland. SIGN 50: a guideline developer's handbook. In: Scottish intercollegiate guidelines network (SIGN), 2014.

11. Bestard O, Lucia M, Crespo E, Van Liempt B, Palacio D, Melilli E, et al. Pretransplant immediately early-1-specific T cell responses provide protection for CMV infection after kidney transplantation. Am J Transplant 2013;13:1793-805.

12. Banas B, Boger CA, Luckhoff G, Kruger B, Barabas S, Batzilla J, et al. Validation of T-Track CMV to assess the functionality of cytomegalovirus-reactive cell-mediated immunity in hemodialysis patients. BMC Immunol 2017;18:15.

13. Costa C, Balloco C, Sidoti F, Mantovani S, Ritta M, Piceghello A, et al. Evaluation of CMVspecific cellular immune response by EliSPOT assay in kidney transplant patients. J Clin Virol 2014;61:523-8.

14. Jarque M, Melilli E, Crespo E, Manonelles A, Montero N, Torras J, et al. CMV-specific cell-mediated immunity at 3-month prophylaxis withdrawal discriminates D+/R+ kidney transplants at risk of late-onset CMV infection regardless the type of induction therapy. Transplantation 2018;102:e472-80.

15. Kumar D, Chin-Hong P, Kayler L, Wojciechowski D, Limaye AP, Osama Gaber A, et al. A prospective multicenter observational study of cell-mediated immunity as a predictor for cytomegalovirus infection in kidney transplant recipients. Am J Transplant 2019;19:2505-16.

16. Kwon JS, Kim T, Kim SM, Sung H, Shin S, Kim YH, et al. Comparison of the commercial QuantiFERON-CMV and overlapping peptide-based ELISPOT assays for predicting CMV infection in kidney transplant recipients. Immune Netw 2017;17:317-25.

17. Lee H, Park KH, Ryu JH, Choi AR, Yu JH, Lim J, et al. Cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in seropositive kidney transplant recipients. PLoS One 2017;12:e0189488.

18. Leone F, Gigliotti P, Mauro MV, Lofaro D, Greco F, Tenuta R, et al. Early cytomegalovirusspecific T-cell response and estimated glomerular filtration rate identify patients at high risk of infection after renal transplantation. Transpl Infect Dis 2016;18:191-201.

19. Lúcia M, Crespo E, Melilli E, Cruzado JM, Luque S, Llaudó I, et al. Preformed frequencies of cytomegalovirus (CMV)-specific memory T and B cells identify protected CMV-sensitized individuals among seronegative kidney transplant recipients. Clin Infect Dis 2014;59:1537-45.

20. Mattes FM, Vargas A, Kopycinski J, Hainsworth EG, Sweny P, Nebbia G, et al. Functional impairment of cytomegalovirus specific CD8 T cells predicts high-level replication after renal transplantation. Am J Transplant 2008;8:990-9.

21. Nesher L, Shah DP, Ariza-Heredia EJ, Azzi JM, Siddiqui HK, Ghantoji SS, et al. Utility of the enzyme-linked immunospot interferon-gamma-release assay to predict the risk of cytomegalovirus infection in hematopoietic cell transplant recipients. J Infect Dis 2016;213:1701-7.

22. Schachtner T, Stein M, Reinke P. CMV-specific T cell monitoring offers superior risk stratification of CMV-seronegative kidney transplant recipients of a CMV-seropositive donor. Transplantation 2017;101:e315-25.

23. Shin KH, Lee HJ, Chang CL, Kim EJ, Lim S, Lee SJ, et al. CMV specific T cell immunity predicts early viremia after liver transplantation. Transpl Immunol 2018;51:62-5.

24. Yong MK, Cameron PU, Slavin M, Morrissey CO, Bergin K, Spencer A, et al. Identifying cytomegalovirus complications using the Quantiferon-CMV assay after allogeneic hematopoietic stem cell transplantation. J Infect Dis 2017;215:1684-94.

25. Cantisan S, Lara R, Montejo M, Redel J, Rodriguez-Benot A, Gutierrez-Aroca J, et al. Pretransplant interferon-gamma secretion by CMV-specific CD8+ T cells informs the risk of CMV replication after transplantation. Am J Transplant 2013;13:738-45.

26. Fernández-Ruiz M, Rodríguez-Goncer I, Parra P, Ruiz-Merlo T, Corbella L, López-Medrano F, et al. Monitoring of CMV-specific cell-mediated immunity with a commercial ELISA-based interferon-γ release assay in kidney transplant recipients treated with antithymocyte globulin. Am J Transplant 2020;20:2070-80.

27. Gabanti E, Lilleri D, Scaramuzzi L, Zelini P, Rampino T, Gerna G. Comparison of the T-cell response to human cytomegalovirus (HCMV) as detected by cytokine flow cytometry and QuantiFERON-CMV assay in HCMV-seropositive kidney transplant recipients. New Microbiol 2018;41:195-202. .

28. Manuel O, Husain S, Kumar D, Zayas C, Mawhorter S, Levi ME, et al. Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study. Clin Infect Dis 2013;56:817-24.

29. Paouri B, Soldatou A, Petrakou E, Theodosaki M, Tsentidis C, Kaisari K, et al. QuantiferonCytomegalovirus assay: a potentially useful tool in the evaluation of CMV-specific CD8+ T-cell reconstitution in pediatric hematopoietic stem cell transplant patients. Pediatr Transplant 2018;22:e13220.

30. Sood S, Haifer C, Yu L, Pavlovic J, Gow PJ, Jones RM, et al. Targeted individual prophylaxis offers superior risk stratification for cytomegalovirus reactivation after liver transplantation. Liver Transpl 2015;21:1478-85.

31. Sood S, Haifer C, Yu L, Pavlovic J, Gow PJ, Jones RM, et al. Early viral-specific T-cell testing predicts late cytomegalovirus reactivation following liver transplantation. Transpl Infect Dis 2018;20:e12934.

32. Thompson G, Boan P, Baumwol J, Chakera A, MacQuillan G, Swaminathan S, et al. Analysis of the QuantiFERON-CMV assay, CMV viraemia and antiviral treatment following solid organ transplantation in Western Australia. Pathology 2018;50:554-61.

33. Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, et al. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018;102:900-31.

34. Razonable RR and Humar A. Cytomegalovirus in solid organ transplant recipients-guidelines of the American society of transplantation infectious diseases community of practice. Clin Transplant 2019;33:e13512.

35. Ruan Y, Guo W, Liang S, Xu Z, Niu T. Diagnostic performance of cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in kidney transplantation: a PRISMA-compliant article. Medicine 2019;98:e15228.