Unraveling the biologic basis of late-onset cytomegalovirus disease in high-risk organ transplant recipients.

Late-onset cytomegalovirus (CMV) disease, defined as CMV disease occurring after 3 months posttransplant is a significant complication with the use of prophylaxis, particularly in R /D patients (1– 4). The incidence of late-onset CMV disease in the valganciclovir era is substantially higher with prophylaxis than with preemptive therapy (5). The risk of late-occurring CMV disease is also higher with a more completely suppressive antiviral regimen (6). Although precise reasons for these observations are not known, preemptive therapy by its inherent design allows controlled viral replication to occur and this antigen exposure could potentially result in enhancement of CMV-specific immunity critical in the long-term control of virus (7). A limited number of studies have assessed CMVspecific immunity in R /D patients receiving prophylaxis. CD8 T-cell interferonresponse to pp65 and immediate early (IE)-1 antigens was documented in all 17 R /D liver transplant recipients; however, neither predicted late-onset CMV disease (8). Although viremia level more than 1000 copies/mL correlated with current CMV disease, viral loads performed 2 to 4 weeks prior were not predictive of disease (8). Assessment of CD8 T cells using 21-peptide pool Quantiferon assay documented detectable responses in 35% of the R or D patients who had received prophylaxis (9). Among patients with CMV disease, 83% (15/18) had negative responses before the onset of CMV disease (9). In R /D subgroup, the incidence of positive responses was 20%. CMV disease occurred in 31% of patients; 14% in patients with positive responses and 36% in those with negative responses (P 0.39). Taken together, these data document a variable and often a low rate of detectable CMV-specific immune responses in high-risk patients receiving prophylaxis. Further, these responses did not consistently predict late-onset CMV disease. BenMarzouk-Hidalgo et al. (10) showed that CMVspecific immunity developed a median of 12 weeks posttransplant in all 21 R /D transplant recipients who received preemptive therapy with valganciclovir. Viral loads were lower after the acquisition of antiviral immunity when compared with before, and the episodes of viremia after the development of CMV-specific immunity resolved spontaneously; none developed late-onset CMV disease at 12 months. Given that there was no comparator or control group with CMV disease, it cannot be incontrovertibly concluded that the immune responses were necessarily protective, only that they were detectable in a cohort who did not develop CMV disease. Although the use of T-cell-depleting agent had no effect on CMV-specific immunity in a previous study (11), the findings of this study must be interpreted in context of the fact that none of the patients received T-cell-depleting agent– based immunosuppression (10). Finally, the effect of controlled viral replication after the development of CMVspecific responses on outcomes other than late-onset CMV disease is not known. Nevertheless, the provocative findings of this study demonstrate that such a response is frequently detectable following preemptive therapy with potentially beneficial immunologic effects against CMV disease. That exposure to the virus facilitates CMV-specific immune reconstitution has also been shown in another study (11). CMV-specific immune responses remained undetectable in 13 R /D patients throughout the period of prophylaxis (11). Only 5 of the 13 patients gained immune reconstitution by 360 days and in all, viremia preceded the appearance of detectable immunity. On the other hand, R patients who received preemptive therapy displayed progressive increase in CMV immunity after 60 days with fully recovered responses in a majority by 180 to 360 days. CMV viremia even at low level boosted immune recovery in R patients. These data suggest that (i) low-grade viremia enhanced immunity in R patients receiving preemptive therapy, (ii) viral suppression in R patients receiving prophylaxis may impair immune priming, and (iii) virus exposure contributed to Tcell recovery in R patients who ultimately gained detectable CMV-specific T-cell responses. Although interferonproduction is important, antigen-specific CD8 T cells are functionally heterogenous and multifunctional T cells are superior surrogates of antiviral host defense than single cytokine assessments of T cells (12, 13). Generation of multifunctional CMV-specific T-cell immunity was more robust in D or R compared with Department of Medicine, Division of Infectious Diseases, Pittsburgh VA Healthcare System and University of Pittsburgh, Pittsburgh, PA. Dr. Singh has received investigator-initiated grant support from CSL Behring. Address correspondence to: Nina Singh, M.D., VA Pittsburgh Healthcare System, University drive C, Pittsburgh, PA 15240. E-mail: nis5@pitt.edu Received January 20, 2011. Accepted January 25, 2011. Copyright © 2011 by Lippincott Williams & Wilkins ISSN 0041-1337/11/9108-825 DOI: 10.1097/TP.0b013e3182126eb9