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Migrating From Universal to Personalized Prevention

Predicting the Risk of Cytomegalovirus Infection After Organ Transplantation

Kotton, Camille Nelson, MD1

doi: 10.1097/TP.0000000000002422
Commentaries

The use of CMV-specific cell-mediated immunity to predict the risk of infection after the end of prophylaxis in CMV seropositive recipients is now possible. The commentator suggests that this testing in prevention protocols is useful and might be incorporated by programs.

1 Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Received 9 August 2018.

Accepted 12 August 2018.

The author declares no funding or conflicts of interest.

Correspondence: Camille Nelson Kotton, MD, Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, 5 Fruit St, Cox 5, Boston, MA 02114. (ckotton@partners.org).

The ability to accurately predict the risk of infection after transplant would enhance individual and programmatic management and outcomes. At present, for prevention of cytomegalovirus (CMV) infection after solid-organ transplant (SOT), we provide universal prophylaxis or preemptive therapy, where cohorts of similar patients are treated in the same manner, with an excess of prophylactic medications and diagnostics used to prevent infection in the subset that will develop infection.1 Late CMV, which may develop within several months after the end of prophylaxis, remains an Achilles heel of SOT, because current CMV diagnostics, such as serology and viral load, do not allow us to predict who is at risk for infection. Focusing methods of prevention on those at higher need would likely decrease medication related toxicities, diagnostic hassles, and associated costs, as well as the associated indirect effects of CMV infection, which can negatively impact transplant outcomes. There are multiple CMV-specific cell-mediated immunity (CMI) assays available which may be able to help us hone in on the at-risk population.1

In this issue, Jarque et al report their results from a prospective trial evaluating CMV-specific CMI in 96 CMV seropositive kidney transplant recipients (R+) who received organs from seropositive donors (D+).2 All underwent 3 months of prophylaxis with valganciclovir followed by preemptive therapy with systematic screening for CMV viremia every 2 weeks until 6 months after transplantation (an approach called “surveillance after prophylaxis” in the updated CMV guidelines1). CMV-specific CMI testing was done periodically and at the end of prophylaxis, using the T-spot.CMV assay (Oxford Immunotec, Inc). Higher immunologic risk recipients were given rabbit antithymocyte globulin (rATG), whereas those at lower risk had receptor antibody (IL2RA) induction therapy. Fourteen (14.6%) of 96 and 2 (2.1%) of 96 developed late-onset CMV infection and disease, respectively; they had significantly lower IFN-γ–producing T-cell frequencies against both IE-1 and pp65 CMV antigens than patients that did not. Choice of induction therapy did not impact T-spot. CMV results in those with or without CMV infection.

Quantifying the predictive thresholds for CMI assays can be challenging, as it juxtaposes sensitivity and specificity with negative and positive predictive values. Using receiver operating characteristic (ROC) curve analyses and data from the end of prophylaxis (3 months after transplant), the authors were able to categorize subjects as high risk (negative testing against both antigens, 21%), intermediate risk (negative result against one antigen, 23%) and low risk (positive dual antigen testing, 56%). Of those cohorts, 35%, 18%, and 6%, respectively, developed late onset CMV infection. IE-1 was a more predictive antigen compared with pp65, and at a lower threshold (25 and 130 IFN-γ spots, respectively), however the combination was statistically more meaningful than either one used alone.

Whether earlier measurements were useful was evaluated just before transplant, and then 15 days and a month after transplant. A poor correlation between pretransplant CMV-specific CMI, especially against IE-1, and the different posttransplant time points was noted in those who received rATG; conversely, a strong positive correlation was observed among anti-IL2RA-treated patients, who were noted to generally maintain their same CMI risk score at all time points. After transplant, rATG-treated recipients had profound abrogation of CMV-specific CMI compared with anti-IL2RA; although not statistically significant, it is interesting that the rATG cohort started off with a lower number of spot counts for each antigen, suggesting that some preexisting host factors may contribute, in addition to induction therapy. Although both cohorts had a decline in CMV-specific CMI shortly after transplant, this was regained by month 3, suggesting that universal prophylaxis during this vulnerable period with subsequent evaluation of CMV-specific CMI may be a practical approach, especially in those who get rATG. Earlier cessation of prophylaxis in those who get anti-IL2RA induction may be possible, based on this data, although future studies would be needed to demonstrate that.

Although rates of CMV infection and disease are lower among CMV D+R+ compared with D+R−, the serologic combination (D+R+) used in this study accounts for the largest cohort internationally, and is the second highest risk for CMV infection (after D+R−).1,3 Diminishing CMV infections in this cohort would likely result in a significant reduction in the impact of both the direct and indirect effects of CMV, including lower rates of morbidity and mortality, with better transplant outcomes. It’s unfortunate that in their study, pretransplant testing was not predictive of CMV infection, as that would be clinically very useful, and might even avoid prophylaxis in those who are likely protected from infection.

No predictive test will be flawless. Whether an infection rate of 6% to 9% (based on a negative predictive value of 91-94%) is acceptable to the transplant community remains to be determined. In this study, 17% developed CMV infection or disease; if the assay had been used, of those with positive dual antigen testing, this would have been reduced to 6% to 9%. The ROC could be tweaked to increase the negative predictive value, although with some change in sensitivity and specificity. Convenience, cost, and integration into clinical management will all be factors that influence the adoptability of this assay.

In those with negative or intermediate CMI, whether prolonged prophylaxis or monitoring with “surveillance after prophylaxis” would be effective, perhaps until such time as robust CMV-specific CMI develops, remains to be studied. In the only interventional trial using CMV-specific CMI to determine management after the end of treatment of viremia, several months of secondary prophylaxis given to those with low CMV-specific CMI was not found to prevent viremia.4

Overall, the results by Jarque et al2 represent a major advance in deciphering the role of CMV-specific CMI in predicting the risk of infection after the end of prophylaxis in CMV seropositive recipients. Programs may feel comfortable including this testing in their prevention protocols, such that they can focus their attention on those recipients who need closer follow-up. Next steps could include development of an equation with multiple factors predictive of CMV infection after SOT, such as CMV CMI, serology, type of induction, mycophenolate mofetil and tacrolimus dosing, numbers of transplants, type of donor, immunological risk, biopsy-proven acute rejection, and delayed or current graft function. We are advancing closer to personalized transplant medicine.

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REFERENCES

1. Kotton CN, Kumar D, Caliendo AM, et al. The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation. 2018;102:900–931.
2. Jarque M, Melilli E, Crespo E, 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–e480.
3. Kotton CN, Huprikar S, Kumar D. Transplant infectious diseases: a review of the scientific registry of transplant recipients published data. Am J Transplant. 2017;17:1439–1446.
4. Kumar D, Mian M, Singer L, et al. An interventional study using cell-mediated immunity to personalize therapy for cytomegalovirus infection after transplantation. Am J Transplant. 2017;17:2468–2473.
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