Cytomegalovirus reactivation and the host immune response in patients with sepsis

OBJECTIVES: We aimed to compare host response profiles between sepsis patients who develop cytomegalovirus (CMV) reactivation (reactivators) and those who do not (non-reactivators).

METHODS: We performed a nested case-control study in CMV-seropositive sepsis patients from two Dutch ICUs. Reactivators (plasma CMV ≥100 IU/ml) were matched 1:1 to non-reactivators, based on length of stay until reactivation, disease severity, and other relevant criteria. We analysed 32 plasma biomarkers and whole-blood gene expression on the day of CMV reactivation (or matched time point for non-reactivators), three days prior, and at ICU admission.

RESULTS: We compared 81 reactivators with 81 matched non-reactivators. In reactivators, six soluble immune checkpoint regulators increased longitudinally from three days before to the day of CMV viraemia onset. In contrast, biomarkers reflecting cytokine release, endothelial activation, coagulation, inflammation and organ damage remained stable. Structural equation modelling identified inhibitory checkpoint regulation as the only variable independently associated with CMV reactivation. Gene expression analysis three days before reactivation revealed upregulation of innate immunity, haemostasis, and CMV-related pathways, alongside downregulation of adaptive immunity and cytokine signalling pathways.

CONCLUSIONS: CMV reactivation in sepsis is preceded by broad immune dysregulation. These data provide insight into antiviral immune mechanisms that are impaired prior to reactivation and may inform preventive strategies.