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Critical illness in cirrhotic patients is associated with a poor prognosis and increased susceptibility to infections. Monocyte HLA-DR expression is decreased in cirrhotic patients, but its prognostic value has not been investigated prospectively.Thirty-eight critically ill patients with decompensated liver cirrhosis were included in this prospective study. On admission to the intensive care unit (ICU), inflammatory parameters (C-reactive protein, procalcitonin and lipopolysaccharide-binding protein), interleukin (IL)-10, interferon (IFN)-γ serum levels, tumour necrosis factor (TNF)-α ex vivo stimulation (whole blood assay) and HLA-DR expression on monocytes (FACS analysis) were determined. Immune parameters were furthermore measured every third day until discharge from the ICU or death of the patients.Intensive care unit mortality of the cirrhotic patients was 34.2%. During admission, TNF ex vivo, IFN-γ and HLA-DR expression were lower in non-survivors (all P<0.05), while IL-10 levels were increased in non-survivors compared with survivors (P=0.001). However, individual values clearly overlapped between groups. Prospective analysis revealed that monocyte HLA-DR expression remained stable or increased in survivors, but decreased in non-survivors (P=0.002). A decrease in HLA-DR expression between admission and day 3 was strongly associated with decreased IFN-γ levels and increased ICU mortality (hazard ratio 3.36, P=0.008), mostly owing to late sepsis. This association was independent of the sequential organ failure assessment and model for end-stage liver disease score.Here we establish the relative HLA-DR expression (admission/day 3) as a prognostic marker for ICU mortality in critically ill cirrhotic patients. These results may guide the evaluation of immune-modulating therapies in these patients.