91 Host response in patients with ICU-acquired pneumonia into the study. In cases, a follow up blood sample was obtained on the day the pneumonia was diagnosed (event); in controls, a follow up sample (” event”) was drawn on day 7 after enrolment into the study. Data are expressed as mean estimate with 95 percent confidence interval, derived from the linear mixed model. Asterisks indicate differences between groups (*P <0.05. **P <0.01. ***P <0.001). Definition of abbreviations: CD = cluster of differentiation; IL = interleukin; MMP = matrix metalloproteinase; RA = receptor antagonist; RAGE = receptor for advanced glycation endproducts; s = soluble; TREM = triggering receptor expressed on myeloid cells; VCAM = vascular cell adhesion protein. Host response proteins at the time of ICU-acquired pneumonia diagnosis relative to controls We next compared host response proteins in cases at the time of the diagnosis of ICUacquired pneumonia with those in controls at day 7 after inclusion. Of 277 cases, 248 event samples (89.5%) were obtained at the day of ICU-acquired pneumonia diagnosis (at a median of 6 days [IQR, 4-10] after ICU admission. Of 632 controls, 307 follow up samples (48.6% of all selected controls, 93.3% of the 329 controls still in the ICU) were obtained on day 7 after inclusion (8 [7-8] days after ICU admission) and available (Figure 1); of 303 controls who were not in the ICU anymore at day 7, 234 had been discharged and 68 had died (no data available for one patient). Analyzing the same four pathophysiological domains at the time of the event, differences were more profound in cases compared to controls than at baseline (Additional file 1: Figure S2). Cytokine levels (IL-6, IL-8, IL-1RA) were higher in cases than controls; IL-10 levels were not different between groups; regarding systemic inflammation procalcitonin, MMP-8, sTREM-1, sRAGE and tenascin-C were higher in cases, whilst sCD163 was not different between groups (Figure 2; Additional file 1: Figure S3). In the endothelial domain, cases had higher levels of sE-selectin, sVCAM-1, fractalkine, sThrombomodulin and angiopoietin-2; other endothelial cell markers (syndecan-1, angiopoietin-1) were similar between groups (Figure 2; Additional file 1: Figure S4). The levels of the coagulation marker sTissue factor but not D-dimer were higher in cases than controls (Figure 2; Additional file 1: Figure S4). Similar results were obtained after adjustment for potential confounders (Additional file 1: Table S4). Together these results suggest that the presence of ICUacquired pneumonia is associated with stronger host response protein aberrations as compared to critical illness in the absence of ICU-acquired pneumonia. Host response protein trajectories We next sought to obtain insight into host response protein trajectories from baseline to the diagnosis of ICU-acquired pneumonia, and differences with host response protein trajectories in controls remaining in the ICU without acquiring pneumonia. With regard to cytokine release and systemic inflammation IL-1RA, tenascin-C, and sCD163 increased from baseline to the day of pneumonia diagnosis, IL-6, IL-10, procalcitonin and sRAGE decreased, and IL-8, MMP-8, and sTREM-1 remained unchanged in cases (Figure 2). With regard to endothelial cell and procoagulant responses, sVCAM-1, fractalkine, syndecan-1, angiopoietin-1 and D-dimer increased from baseline to event, and sE-selectin, sThrombomodulin, angiopoietin-2, and sTissue factor remained unchanged in cases (Figure 2). In controls, cytokine release and systemic inflammation responses decreased from baseline until day 7 (IL-6, IL-10, procalcitonin, and sRAGE), whilst sCD163 increased over time. Endothelial cell and procoagulant responses in 5
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