Cytomegalovirus: Why Viral Dynamics Matter

Contrary to bacterial replicating kinetics, where the doubling time 1.3 days, the proportion of patient with a high viral load would have varies considerably but often ismeasured inminutes or hours, viral replication kinetics is calculated in days. A new study by Isabelle Lodding and colleagues in E-Biomedicine attempts to calculate the doubling time of cytomegalovirus (CMV) in a cohort of solid organ and stem cell recipients (Lodding et al., 2015). Why does the doubling time of CMVmatter? This number is of great interest to the transplant specialist, as the preemptive treatment approach relies on the detection of replicating CMV in blood before disease occurs. Regular determination of quantitative CMV PCR testing allows selecting those patients with reactivation of CMV in need of a preemptive treatment. Often, a quantitative CMV copy threshold in blood is used to start antiviral treatment. Neither the optimal frequency of CMV testing nor the ideal source of CMV PCR (whole blood, or plasma), nor the optimal threshold has been established. Thus, protocols between transplant centers vary. The recently published updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation recommended weekly testing for 3–4 months, with moderate evidence (Kotton et al., 2013). For most centers, however, it would be very difficult to adhere to such a tight schedule, in particular later after transplantation. Therefore, a precise knowledge of the doubling timewould allow to safely widen the interval between CMV PCR testing, without an increase in CMV disease episodes. The main finding of the study by Lodding and colleagues is a CMV doubling time of 4.3 days (median, IQR 2.5–7.8), which in contrast to earlier studies is considerably longer. Neither the donor–recipient CMV sero-constellation nor the type of transplant did influence these results. Earlier studies by V. Emery and P. Griffiths in bonemarrow transplant patients estimated a shorter doubling time of CMV of 1.5 days (median, range 0.38–4.7) (Emery et al., 1999). Similar doubling times were calculated in a cohort of liver transplant recipients (2 days (median, 0.1–69)) (Nebbia et al., 2007). Many factors may have influenced these different estimates, including the intensity of immunosuppression, the type of sample used for CMV PCR detection, frequency of measurement, type of transplantation, or percentage of patients at high risk for CMV reactivation. While some are less likely than other to play a role, data on the influence of these factors on the doubling time are conflicting. Interestingly, in their simulation model, Lodding and colleagues were able to predict their real rate of recipients with a high CMV viral load (1.4%, arbitrarily set at N18,200 IU/mL) with the assumption of their lower doubling time of 4.3 days. Using a shorter doubling time of