Current Understanding of Cytomegalovirus Reactivation in Critical Illness

Abstract

Cytomegalovirus (CMV) reactivation has been described in adults with critical illness caused by diverse etiologies, especially severe sepsis, and observational studies have linked CMV reactivation with worse clinical outcomes in this setting. In this study, we review observational clinical data linking development of CMV reactivation with worse outcomes in patients in the intensive care unit, discuss potential biologically plausible mechanisms for a causal association, and summarize results of initial interventional trials that examined the effects of CMV prevention. These data, taken together, highlight the need for a randomized, placebo-controlled efficacy trial (1) to definitively determine whether prevention of CMV reactivation improves clinical outcomes of patients with critical illness and (2) to define the underlying mechanism(s).

Keywords: Cytomegalovirus; acute respiratory distress syndrome; critical illness; sepsis.

Figure 1.

Pooled effect estimates of the association between cytomegalovirus (CMV) reactivation and intensive care unit mortality across multiple studies [6]. The odds ratio of overall mortality among patients with CMV reactivation relative to those with no reactivation was 2.02; above, improved survival was associated with no reactivation of CMV. CI, confidence interval. Reproduced from Lachance et al. Association between cytomegalovirus reactivation and clinical outcomes in immunocompetent critically ill patients: a systemic review and meta-analysis. Open Forum Infect Dis 2017;4:ofx029, by permission of Oxford University Press.

Figure 2.

Cumulative incidence of cytomegalovirus (CMV) viremia by intensive care unit (ICU) at 2 centers in a prospective study of CMV reactivation across multiple types of intensive care [4]. Reproduced with permission from Limaye et al. Cytomegalovirus reactivation in critically Ill immunocompetent patients. JAMA 2008;300:413–22. Copyright©(2008) American Medical Association. All rights reserved.

Figure 3.

Predicted probability of death or continued hospitalization by day 30 as a function of average cytomegalovirus (CMV) area under the curve (AUC), adjusted for unit and baseline ventilator use, from a 2-center, prospective observational study of CMV reactivation in the intensive care unit [4]. Conversion between IU/mL and copies/mL is 1.4 copies/IU. Reproduced with permission from Limaye et al. Cytomegalovirus reactivation in critically Ill immunocompetent patients. JAMA 2008;300:413–422. Copyright©(2008) American Medical Association. All rights reserved.

Figure 4.

In a murine model of sepsis caused by cecal ligation and puncture, murine cytomegalovirus-seropositive mice were given ganciclovir at varying doses and evaluated for pulmonary fibrosis. Lungs were fixed, embedded, sectioned, and stained, and images were acquired and color segmented, and fibrosis was quantitated as percentage of pixels. Each bar represents mean ± standard error for 5–7 mice [27]. Reprinted from Forster et al. Antiviral prevention of sepsis induced cytomegalovirus reactivation in immunocompetent mice. Antivir Res 2010;85:496–503, with permission from Elsevier.

Figure 5.

Schematic of proposed mechanisms for how cytomegalovirus (CMV) reactivation in patients with sepsis could be causally associated with worse clinical outcomes. ICU, intensive care unit.

Figure 6.

Decreased cytomegalovirus (CMV) reactivation after ganciclovir/valganciclovir in a phase II, randomized, placebo-controlled, clinical trial [17]. Reproduced with permission from Limaye et al. Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial. JAMA 2017;318:731–740. Copyright©(2017) American Medical Association. All rights reserved.