Infect Chemother.  2015 Jun;47(2):105-110. 10.3947/ic.2015.47.2.105.

Diagnostic Usefulness of Cytomegalovirus (CMV)-Specific T Cell Immunity in Predicting CMV Infection after Kidney Transplantation: A Pilot Proof-of-Concept Study

• Kim SH
• Lee HJ
• Kim SM
• Jung JH
• Shin S
• Kim YH
• Sung H
• Lee SO
• Choi SH
• Kim YS
• Woo JH
• Han DJ

• KMID: 2068994
• DOI: http://doi.org/10.3947/ic.2015.47.2.105

Abstract

BACKGROUND
Cytomegalovirus (CMV) is one of the most important opportunistic infections in transplant recipients. Currently sero-positivity for CMV IgG before solid organ transplantation is the laboratory test of choice for stratifying the risk of CMV reactivation after solid organ transplantation. Theoretically, CMV-specific cell-mediated immune responses before solid organ transplantation should further categorize patients as high or low risk of CMV development. We therefore evaluated the usefulness of the CMV-specific enzyme-linked immunospot (ELISPOT) assay in kidney transplant (KT) candidates for predicting the development of CMV infections after transplantation.
MATERIALS AND METHODS
All adult CMV IgG (+) recipients admitted to the KT institute between March 2014 and June 2014 were enrolled, and CMV infections after KT were observed between March 2014 and December 2014. All patients underwent CMV pp65 and IE1-specific ELISPOT assays before transplantation. CMV infection was defined in the presence of CMV antigenemia, CMV syndrome, or tissue-invasive CMV disease. We used the data to select optimal cut-off values for pp65 and IE1, respectively, on ROC curves.
RESULTS
A total of 69 transplant recipients involving 54 (78%) living-donor KT, 9 (13%) deceased-donor KT, 3 (4%) kidney-pancreas transplants, and 3 (4%) pancreas transplants were enrolled. Of the 69 patients, 27 (39%) developed CMV infections. There was no association between the IE1-specific ELISPOT assay and CMV infection. However, only 15 (31%) of the 48 patients with positive pp65-specific ELISPOT results (>10 spots/2.0 x 105 cells) developed CMV infections, whereas 12 (57%) of the 21 patients with negative pp65-specific ELISPOT results developed CMV infection (P = 0.04).
CONCLUSION
Negative pp65-specific ELISPOT assay results before transplantation appear to predict the subsequent development of CMV infections after transplantation in CMV IgG (+) KT recipients. Therefore, risk stratification of CMV IgG (+) recipients using the CMV-specific ELISPOT, together with preventive strategies, may further reduce CMV development.

Keyword

Cytomegalovirus; Enzyme-linked immunospot assay; Kidney transplantation

MeSH Terms

Adult
Cytomegalovirus*
Enzyme-Linked Immunospot Assay
Humans
Immunoglobulin G
Kidney
Kidney Transplantation*
Opportunistic Infections
Organ Transplantation
Pancreas
ROC Curve
Transplantation
Transplants
Immunoglobulin G

Figure

• 

  Figure 1 Flow chart of the study. LDKT, living-donor kidney transplantation; DDKT, deceased-donor kidney transplantation; PKT, pancreas-kidney transplantation. CMV, cytomegalovirus; ELISPOT, enzyme-linked immunospot.

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  Figure 2 Response to IE1 and pp65 according to the presence of CMV infection after kidney transplantation. Bars indicate medians. The Mann-Whitney U test was used to compare the differences between groups. IFN, interferon; PBMC, peripheral blood mononuclear cells; CMV, cytomegalovirus.

Reference

1. Razonable RR, Humar A. AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant. 2013; 13:Suppl 4. 93–106.

2. Bestard O, Lucia M, Crespo E, Van Liempt B, Palacio D, Melilli E, Torras J, Llaudó I, Cerezo G, Taco O, Gil-Vernet S, Grinyó JM, Cruzado JM. PRetransplant immediately early-1-specific T cell responses provide protection for CMV infection after kidney transplantation. Am J Transplant. 2013; 13:1793–1805.

3. Hahn JS, Lee SJ, Park WK, Ko YW, Kim HO, Lee SY. A survey on the cytomegalovirus antibodies in blood donors and the diseased. Korean J Blood Transfus. 1990; 1:21–34.

4. Mori T, Okamoto S, Matsuoka S, Yajima T, Wakui M, Watanabe R, Ishida A, Iwao Y, Mukai M, Hibi T, Ikeda Y. Risk-adapted pre-emptive therapy for cytomegalovirus disease in patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant. 2000; 25:765–769.

5. Jang EY, Park SY, Lee EJ, Song EH, Chong YP, Lee SO, Choi SH, Woo JH, Kim YS, Kim SH. Diagnostic performance of the cytomegalovirus (CMV) antigenemia assay in patients with CMV gastrointestinal disease. Clin Infect Dis. 2009; 48:e121–e124.

6. Moon SM, Sung H, Kim MN, Lee SO, Choi SH, Kim YS, Woo JH, Kim SH. Diagnostic yield of the cytomegalovirus (CMV) antigenemia assay and clinical features in solid organ transplant recipients and hematopoietic stem cell transplant recipients with CMV pneumonia. Transpl Infect Dis. 2012; 14:192–197.

7. Kim SH, Cho OH, Park SJ, Lee EM, Kim MN, Lee SO, Choi SH, Kim YS, Woo JH, Lee SA, Kang JK. Rapid diagnosis of tuberculous meningitis by T cell-based assays on peripheral blood and cerebrospinal fluid mononuclear cells. Clin Infect Dis. 2010; 50:1349–1358.

8. Kumar D, Chernenko S, Moussa G, Cobos I, Manuel O, Preiksaitis J, Venkataraman S, Humar A. Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients. Am J Transplant. 2009; 9:1214–1222.

9. Manuel O, Husain S, Kumar D, Zayas C, Mawhorter S, Levi ME, Kalpoe J, Lisboa L, Ely L, Kaul DR, Schwartz BS, Morris MI, Ison MG, Yen-Lieberman B, Sebastian A, Assi M, Humar A. 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; 56:817–824.

10. Bunde T, Kirchner A, Hoffmeister B, Habedank D, Hetzer R, Cherepnev G, Proesch S, Reinke P, Volk HD, Lehmkuhl H, Kern F. Protection from cytomegalovirus after transplantation is correlated with immediate early-1-specific CD8 T cells. J Exp Med. 2005; 201:1031–1036.

11. Malouli D, Hansen SG, Nakayasu ES, Marshall EE, Hughes CM, Ventura AB, Gilbride RM, Lewis MS, Xu G, Kreklywich C, Whizin N, Fischer M, Legasse AW, Viswanathan K, Siess D, Camp DG 2nd, Axthelm MK, Kahl C, DeFilippis VR, Smith RD, Streblow DN, Picker LJ, Früh K. Cytomegalovirus pp65 limits dissemination but is dispensable for presistence. J Clin Invest. 2014; 124:1928–1944.

12. Nickel P, Bold G, Presber F, Biti D, Babel N, Kreutzer S, Pratschke J, Schönemann C, Kern F, Volk HD, Reinke P. High levels of CMV-IE-1-specific memory T cells are associated with less alloimmunity and improved renal allograft function. Transpl Immunol. 2009; 20:238–242.

13. Egli A, Binet I, Binggeli S, Jäger C, Dumoulin A, Schaub S, Steiger J, Sester U, Sester M, Hirsch HH. Cytomegalovirus-specific T-cell responses and viral replication in kindey transplant recipients. J Transl Med. 2008; 6:29.

14. Pipeling MR, John ER, Orens JB, Lechtzin N, McDyer JF. Primary cytomegalovirus phosphoprotein 65-specific CD8+ T-cell responses and T-bet levels predict immune control during early chronic infection in lung transplant recipients. J Infect Dis. 2011; 204:1663–1671.