89 Host response in patients with ICU-acquired pneumonia parametric data were analyzed using a Student t test; a P value < 0.05 was considered statistically significant. aNeutrophil, monocyte, and lymphocyte counts missing in up to 47% of patients (considered missing at random), see Additional file 1: Table S2 for details. Baseline host response protein differences between patients who did and those who did not develop an ICU-acquired pneumonia Our first study objective was to obtain insight into host response protein differences between cases and controls prior to development of ICU-acquired pneumonia in the former group. 39 cases (12.3%) were enrolled in ASPIRE-ICU on the day ICU-acquired pneumonia was diagnosed; these patients were excluded from the biomarker analysis since a blood sample prior to development of pneumonia was lacking (Figure 1). Of the remaining 277 cases, 272 baseline blood samples (98.2%) were obtained 2 [1-2] days (median [IQR]) after ICU admission, and 4 [2-8] days prior to the diagnosis of ICUacquired pneumonia (Additional file 1: Figure S1). From 632 controls 624 baseline blood samples (98.7%) were available, drawn 2 [1-2] days after ICU admission. We analyzed 19 biomarkers reflective of four pathophysiological pathways implicated in host response aberrations during severe infection: cytokine release and systemic inflammation, and endothelial cell and procoagulant responses. On all four domains cases and controls already differed at baseline (Additional file 1: Figure S2). Baseline plasma levels of the cytokines IL-6 and IL-1RA were higher in cases than controls, while the plasma concentrations of IL-8 and the anti-inflammatory cytokine IL-10 were not different between groups. Likewise, systemic inflammation markers procalcitonin, MMP-8, sTREM-1, and sRAGE were higher at baseline in cases, whilst tenascin-C and sCD163 concentrations were not different between groups (Figure 2; for direct comparison see Additional file 1: Figure S3). Cases also displayed higher levels of the endothelial cell markers fractalkine and angiopoietin-2 (indicative of disturbed endothelial barrier function), whilst other endothelial cell markers (sE-selectin, sVCAM-1, sThrombomodulin, syndecan-1, angiopoietin-1) were similar between groups. Regarding coagulation markers, baseline sTissue factor levels were higher in cases; D-dimer was similar between groups (Figure 2; for direct comparison see Additional file 1: Figure S4). Similar results were obtained after adjustment for potential confounders (Additional file 1: Table S4). Collectively, these data show that patients who later during their ICU stay develop pneumonia have more exaggerated host response protein aberrations at baseline than those who do not acquire pneumonia. 5
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