92 Chapter 5 controls increased (syndecan-1, angiopoietin-1, and D-dimer), and angiopoietin-2 decreased. Importantly, directly comparing biomarker trajectories between cases and controls revealed several differences: the levels of IL-6, procalcitonin, sRAGE, and angiopoietin-2 decreased less strongly over time in cases, while levels of tenascin-C and sVCAM-1 increased in cases but remained stable in controls (Figure 2; Additional file 1: Table S4). These differences in trajectories remained significant after adjusting for potential confounders at baseline (Additional file 1: Table S4). Collectively, these data show that host response protein biomarkers of patients who develop ICU-acquired pneumonia, relative to patients who do not develop ICU-acquired pneumonia, show more strongly altered plasma levels across distinct pathophysiological domains in a sustained way, i.e., from briefly after ICU admission up to the day of the diagnosis of pneumonia. In 122 cases (44% of all cases) the day of the pneumonia occurred prior to day 7 after inclusion (a standard sampling day; Additional file 1: Table S5). In this subgroup we conducted paired analyses across three time points, providing insight in biomarker trajectories after pneumonia diagnosis. The levels of IL-6, procalcitonin, sRAGE, and angiopoietin-2 were lower post-event compared to the day of pneumonia diagnosis, while syndecan-1 and angiopoietin-1 concentrations were higher post-event; the other host response biomarkers remained unaltered (Additional file 1: Figure S5 and S6). These results suggest that, while most responses persist, some inflammatory markers decline and some endothelial markers continue to rise following pneumonia treatment, reflecting the heterogeneity of biomarker trajectories in critically ill patients. Lastly, we explored if host response protein aberrations detected in cases at baseline were influenced by the time interval between admission and the occurrence of pneumonia (Additional file 1: Table S6). We hypothesized that in patients who developed pneumonia shortly after inclusion might show baseline biomarker differences (relative to controls) resulting from an emerging infection of the airways that was not yet detected. For most host response biomarkers we observed nonlinear trends in their trajectories as such that patients who developed ICU-acquired pneumonia either early after admission (2-5 days) or very late (>10 days) showed stronger host response protein changes at baseline as compared to patients who developed pneumonia between 6-10 days (Additional file 1: Figure S7 and S8). Discussion Pneumonia is one of the most common nosocomial infections in the ICU and there is evidence that immune suppression resulting from critical illness puts patients at risk for secondary infections [5–8]. We here examined the possibility that critically ill patients exhibit broad disturbances in their host response across several pathophysiological domains both prior to and during ICU-acquired pneumonia by sequentially measuring 19 protein biomarkers in plasma. We show that plasma biomarker levels, while heterogeneous across time points and patient groups, were different in patients who later during their ICU stay develop pneumonia from to those in patients who do not acquire pneumonia, already shortly after admission as well as in the trajectory toward the day pneumonia is diagnosed.
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