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Matthias Unterberg, Stefan Felix Ehrentraut, Thilo Bracht, Alexander Wolf, Helge Haberl, Alexander von Busch, Katharina Rump, Dominik Ziehe, Maha Bazzi, Patrick Thon, Barbara Sitek, Katrin Marcus-Alic, Malte Bayer, Karin Schork, Martin Eisenacher, Björn Ellger, Daniel Oswald, Frank Wappler, Jérôme Defosse, Dietrich Henzler, Thomas Köhler, Alexander Zarbock, Christian Putensen, Jens-Christian Schewe, Ulrich Frey, Moritz Anft, Nina Babel, Eike Steinmann, Yannick Brüggemann, Mirko Trilling, Andreas Schlüter, Hartmuth Sebastian Burkhard Nowak, Michael Adamzik, Tim Rahmel, Björn Koos

• \(\bf Background\) Sepsis is one of the leading causes of death. Treatment attempts targeting the immune response regularly fail in clinical trials. As HCMV latency can modulate the immune response and changes the immune cell composition, we hypothesized that HCMV serostatus affects mortality in sepsis patients. \(\bf Methods\) We determined the HCMV serostatus (i.e., latency) of 410 prospectively enrolled patients of the multicenter SepsisDataNet.NRW study. Patients were recruited according to the SEPSIS-3 criteria and clinical data were recorded in an observational approach. We quantified 13 cytokines at Days 1, 4, and 8 after enrollment. Proteomics data were analyzed from the plasma samples of 171 patients. \(\bf Results\) The 30-day mortality was higher in HCMV-seropositive patients than in seronegative sepsis patients (38% vs. 25%, respectively; \(\it p\) = 0.008; HR, 1.656; 95% CI 1.135–2.417). This effect was observed independent of age (\(\it p\) = 0.010; HR, 1.673; 95% CI 1.131–2.477). The predictive value on the outcome of the increased concentrations of IL-6 was present only in the seropositive cohort (30-day mortality, 63% vs. 24%; HR 3.250; 95% CI 2.075–5.090; \(\it p\) < 0.001) with no significant differences in serum concentrations of IL-6 between the two groups. Procalcitonin and IL-10 exhibited the same behavior and were predictive of the outcome only in HCMV-seropositive patients. \(\bf Conclusion\) We suggest that the predictive value of inflammation-associated biomarkers should be re-evaluated with regard to the HCMV serostatus. Targeting HCMV latency might open a new approach to selecting suitable patients for individualized treatment in sepsis.