Cytomegalovirus immunity in high-risk liver transplant recipients following preemptive antiviral therapy versus prophylaxis
Danniel Zamora, Sayan Dasgupta, Terry Stevens-Ayers, Bradley Edmison, Drew J. Winston, Raymund R. Razonable, Aneesh K. Mehta, G. Marshall Lyon, Michael Boeckh, Nina Singh, David M. Koelle, Ajit P. Limaye
Danniel Zamora, Sayan Dasgupta, Terry Stevens-Ayers, Bradley Edmison, Drew J. Winston, Raymund R. Razonable, Aneesh K. Mehta, G. Marshall Lyon, Michael Boeckh, Nina Singh, David M. Koelle, Ajit P. Limaye
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Research Article Infectious disease Transplantation

Cytomegalovirus immunity in high-risk liver transplant recipients following preemptive antiviral therapy versus prophylaxis

Abstract

CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R–) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R– LTxR.

Authors

Danniel Zamora, Sayan Dasgupta, Terry Stevens-Ayers, Bradley Edmison, Drew J. Winston, Raymund R. Razonable, Aneesh K. Mehta, G. Marshall Lyon, Michael Boeckh, Nina Singh, David M. Koelle, Ajit P. Limaye

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Figure 6

T cell, NK cell, and humoral immune responses in PET recipients with and without preceding CMV DNAemia.

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T cell, NK cell, and humoral immune responses in PET recipients with and...
Immune parameters at 100 days after transplant in PET recipients (N = 73) stratified by preceding detectable CMV DNAemia by qPCR in the first 100 days after transplant. Patients were grouped according to positive (blue) or negative (red) CMV DNAemia in the first 100 days after transplant. Examined immune parameters included terminally differentiated (A) CD8+ and (B) CD4+ T cell counts based on the expression of CD57; CMV-specific polyfunctional absolute (C) CD8+ and (D) CD4+ T cell counts; COMPASS (E) CD8 and (F) CD4 polyfunctionality scores (PFSs); absolute counts of (G) CD3negCD56brightCD57negNKG2Cpos, (H) CD3negCD56dimCD57negNKG2Cpos, (I) and CD3negCD56dimCD57posNKG2Cpos NK cells; and (J) CMV epithelial cell entry-specific neutralizing antibody (nAb) dilution titers. Polyfunctional T cell counts were defined as those expressing IFN-γ plus at least 1 additional functional marker. Dilution titers were calculated from IC50 values for graphing purposes by taking the antilog2 of each value. For example, an IC50 of 5 corresponds to a CMV nAb dilution titer of 32. For absolute cell counts, 0 values were imputed as a low value (i.e., less than minimum of distribution) for graphing purposes owing to logarithmic scale conversion. Solid black lines represent values, and whiskers represent interquartile range. Comparisons were made using 2-sided Wilcoxon’s rank-sum testing at 95% CI.