Cytomegalovirus: A Troll in the ICU? Overview of the Literature and Perspectives for the Future

Abstract

Cytomegalovirus (CMV) is one of the most pathogenic viruses in human. After a primary infection, CMV resides in the host for life as a latent infection. When immunity is reduced, CMV can escape the suppressive effects of the immune system and lead to viremia and antigenemia. This reactivation, first seen in transplant patients, has also been documented in non-immunocompromised CMV-seropositive critically ill patients and is associated with higher morbidity and mortality. In the latter, it is not clear whether CMV reactivation is an innocent bystander or the cause of this observed worse outcome. Two studies showed no difference in the outcome of CMV-seropositive and seronegative patients. In addition, proof-of-concept studies investigating prophylactic antiviral treatment to prevent CMV reactivation during critical illness, failed to show a beneficial effect on interleukin levels or clinical outcome. Further research is necessary to resolve the question whether CMV replication impairs the prognosis in non-immunocompromised critically ill patients. We here give a concise overview on the available data and propose strategies to further unravel this question. First, post-mortem investigation may be useful to evaluate the effect of viral replication on organ inflammation and function. Second, further research should focus on the question whether the level of viremia needs to exceed a threshold to be associated with worse outcome. Third, clinical and biochemical assessments may help to identify patients at high risk for reactivation. Fourth, preemptive treatment based upon early detection of the virus is currently under investigation. Finally, immune-stimulating biologicals may be beneficial in high-risk groups.

EBV DNA increase in COVID-19 patients with impaired lymphocyte subpopulation count

“…The strict relation between immunosuppression and reactivation of latent viruses and an increased prevalence of opportunistic viral infections is well known, especially in transplanted patients and in ICU patients ( Fishman, 2013 , Schildermans and De Vlieger, 2020 , Limaye and Boeckh, 2010 , Frantzeskaki et al, 2015 , Ong et al, 2017 , Cantan et al, 2019 , Coşkun et al, 2017 ).…”

“…The SARS-CoV-2 influence on immunological response, and its relationship with the reactivation of opportunistic viral infection in the clinical course of COVID-19 is still under investigation. Among various pathogens, opportunistic viral infections such as human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are particularly relevant in immunocompromised patients ( Fishman, 2017 , Fishman, 2013 ) and their reactivation has also been reported in patients in intensive care units (ICU) with no previous immune suppression ( Schildermans and De Vlieger, 2020 , Limaye and Boeckh, 2010 , Frantzeskaki et al, 2015 , Ong et al, 2017 , Cantan et al, 2019 , Coşkun et al, 2017 ).…”

Update in Viral Infections in the Intensive Care Unit

“…The effects of CMV reactivation on adverse clinical outcomes in immunocompetent critically patients have been associated with higher blood viral loads ( 208 ). Although no studies have robustly responded to whether and when CMV reactivation should be treated in this patient population ( 209 ), it has been suggested that therapy should be administered if CMV reactivation is associated with organ-involvement and/or if high viral loads are detected (≥10 3 copies/mL) ( 208 ).…”

“…Two randomized controlled trials assessing the use of prophylactic or preemptive treatment with aciclovir for HSV reactivation in mechanically ventilated patients, found that aciclovir administration did not improve clinical outcomes ( 207 ). As for HSV, two randomized controlled studies (the GRAIL-trial and the CCCC-trial) evaluating the efficacy of preemptive treatment for CMV reactivation in seropositive patients, failed to show benefit in IL-6 levels changes and in clinical outcomes, respectively ( 209 – 211 ). The GRAIL-trial, however, demonstrated that ganciclovir group had significantly more ventilator-free days in the sepsis subgroup analysis ( 209 , 211 ).…”

“…As for HSV, two randomized controlled studies (the GRAILtrial and the CCCC-trial) evaluating the efficacy of preemptive treatment for CMV reactivation in seropositive patients, failed to show benefit in IL-6 levels changes and in clinical outcomes, respectively (209)(210)(211). The GRAIL-trial, however, demonstrated that ganciclovir group had significantly more ventilator-free days in the sepsis subgroup analysis (209,211). Based on expertopinion, it has been suggested that preemptive treatment may be given in patients either at high-risk for HSV or CMV reactivation or in those who already have reactivation but at an early stage, before the advent of clinically evident infection (208).…”