Human cytomegalovirus seropositivity is associated with reduced patient survival during sepsis

Abstract

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.

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.

Results: The 30-day mortality was higher in HCMV-seropositive patients than in seronegative sepsis patients (38% vs. 25%, respectively; p = 0.008; HR, 1.656; 95% CI 1.135-2.417). This effect was observed independent of age (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; 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.

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.

Keywords: HCMV latency; Inflammatory biomarker; Mortality prediction; Sepsis.

Fig. 1

Kaplan–Meier analysis of the impact of HCMV serostatus on the 30-day survival in sepsis

Fig. 2

The prognostic value of IL-6 (a–c) as well as IL-10 (d–f) in our cohort was limited to the CMV seropositive group and was absent in the seronegative cohort

Fig. 3

While procalcitonin, a clinically very relevant biomarker, had a predictive effect in the entire cohort (a), we could not observe a predictive value in the HCMV-seronegative patients (b). PCT is only of predictive value in the HCMV-seropositive cohort (c)

Fig. 4

The plasma proteomics analysis according to survival. a Dot-plot illustrating the statistical analysis of n = 66 HCMV seronegative and n = 105 seropositive patients at days 1 and 4 (Student’s t-test; two-sided, unequal variances). b Volcano plot illustrating plasma proteome quantitation for seropositive patients and days 1 and 4 (p-values corrected according to Benjamini-Hochberg). Significantly regulated proteins (p_FDR value ≤ 0.05, absolute ratio of means ≥ 1.5) highlighted in red and labeled with gene names. c Gene ontology enrichment analysis of proteins regulated in seropositive patients at day 4 (p-value ≤ 0.05, absolute ratio of means ≥ 1.5). d Network representation of regulated proteins passing the p_FDR threshold of 0.05. Selected enriched ontologies (biological process) highlighted. e Scatter plots illustrating plasma proteome dynamics at day 4 for HCMV seronegative and seropositive patients. Proteins significantly regulated in seropositive patients are highlighted in both plots