Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study

Kirsten Van De Groep,On Behalf Of The Mars Consortium ,Marcus J Schultz,Linda M Peelen,Stefan Nierkens,C Erik Hack,Tom Van Der Poll,Olaf L Cremer,David S Y Ong,Peter M C Klein Klouwenberg,Marc J M Bonten

doi:10.1186/s13054-018-2261-0

Kirsten Van De Groep, On Behalf Of The Mars Consortium + Show 9 more

Open Access

https://doi.org/10.1186/s13054-018-2261-0

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Abstract

BackgroundCytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis.MethodsIn this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs−). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma–induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models.ResultsAmong 64 CMV+ patients, 45 could be matched to CMVs+ or CMVs− controls or both. The two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. CMV+ patients had increased IP-10 on day 7 after viremia onset (symmetric percentage difference +44% versus −15% when compared with CMVs+ and +37% versus +4% when compared with CMVs−) and decreased IL-1RA (−41% versus 0% and −49% versus +10%, respectively). However, multivariable analyses did not show an independent association between CMV reactivation and time trends of IL-6, IP-10, IL-10, or IL-1RA.ConclusionCMV reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. Therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-CMV therapy.

Highlights

Cytomegalovirus (CMV) reactivation is observed in 14– 41% of intensive care unit (ICU) patients without known prior immune deficiency [1,2,3] and is associated with increased morbidity and mortality [4,5,6]
We estimated that the population-attributable fraction of ICU mortality due to CMV reactivation was 23% in patients with acute respiratory distress syndrome (ARDS) [7]
In a subsequent study among patients with septic shock, we found an effect of CMV reactivation on ICU mortality only in patients with concurrent Epstein–Barr virus reactivation [8]

Summary

Introduction

Cytomegalovirus (CMV) reactivation is observed in 14– 41% of intensive care unit (ICU) patients without known prior immune deficiency [1,2,3] and is associated with increased morbidity and mortality [4,5,6]. Based on previous studies in ICU patients, there is a clear pathophysiological link between inflammation and immune suppression on the one hand and the subsequent risk of CMV reactivation on the other [9,10,11,12,13]. Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. We studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis

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