94 Chapter 5 studies, with prospective sequential sampling, are warranted to obtain further insight into the immunopathobiology preceding secondary infections in critically ill patients. The current study is different from and expands our earlier investigation in which we reported on ICU-acquired infections in patients with sepsis in several ways [9]. The present study includes a more heterogenous population of critically ill patients with various admission reasons (rather than only sepsis) and focusses on ICU-acquired pneumonia specifically (rather than all ICU-acquired infections combined). We determined biomarker trajectories to the day pneumonia was diagnosed, and in controls to day 7 after enrollment (rather than measurements restricted during the first 4 days after ICU admission). Furthermore, this study enrolled patients from 30 hospitals, both academic and non-academic, across Europe (rather than from two academic hospitals in the Netherlands). The plasma biomarker panels reported in both studies partially overlap (IL-6, IL-8, IL-10, MMP-8, fractalkine, sE-selectin, angiopoietin-1 and -2). As compared with our previous study, in the current analyses additional inflammatory markers (procalcitonin, sTREM-1, sRAGE, tenascin-C), more (specific) endothelial cell markers (sVCAM-1, syndecan-1, sThrombomodulin) and an additional coagulation marker (sTissue factor) were measured, while platelet counts, anticoagulant proteins (antithrombin, protein C) and prothrombin time were not measured. Our study has strengths and limitations. Due to the inclusion criteria the study population was relatively enriched for patients with S. aureus colonization, which may hamper generalization of results. However, adjusting for S. aureus colonization status did not change results on host response differences between cases and controls. We provide information on a large, well-defined, prospectively collected cohort including patients admitted to ICUs throughout 30 hospitals in Europe, which enhances the generalizability of the results. Nonetheless, while representative of a general ICU population, study patients comprised a heterogeneous group with various underlying diseases that may impact biomarker responses. The disease of interest, ICU-acquired pneumonia, was extensively protocol-defined and assessed daily in all enrolled patients. However, the embedding of this large investigation across multiple study sites precluded functional and/or cell-specific measurements requiring fresh samples (e.g., blood leukocyte cytokine production capacity and monocyte HLA-DR expression), and systemic sampling of the airways. Only admission types were registered and specific diagnoses for “medical” admissions were not recorded. Analyses of the biomarker trajectories were limited by the fact that 303 controls (47.9%) were not in the ICU anymore at day 7 due to discharge or death, competing risks that may impact the results in opposite directions.
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