64 Chapter 4 >30 mg/L)) and a new or progressive infiltrate, consolidation, cavitation, or pleural effusion on chest X ray or computed tomography scan [14, 16]. Patients were excluded if there was a hospital-associated pneumonia or clinical suspicion of aspiration pneumonia [16]. Severity scores - the Pneumonia Severity Index (PSI) [17], the Modified Early Warning Score (MEWS) [18] and the quick Sequential Organ Failure Assessment qSOFA score [19] - were calculated upon hospital admission. Age and sex-matched subjects without acute infection served as controls. All participants, or their legal representatives, provided written informed consent and procedures followed were in accordance with the ethical standards of the Helsinki Declaration [20]. Assays Ethylenediaminetetraacetic acid (EDTA) blood (for plasma biomarker measurements) was obtained within 16 hours of hospital admission. A subset of patients was also sampled one month after admission. We measured biomarkers reflective of key host response pathways using a Luminex multiplex assay (R&D Systems Inc, Minneapolis, MN) and BioPlex 200 (BioRad, Hercules, CA): ferritin, CRP, soluble triggering receptor expressed on myeloid cells (sTREM)-1, soluble cluster of differentiation 163 (sCD163), and tenascin-C (reflecting systemic inflammation); myeloperoxidase (MPO), proteinase-3 and neutrophil gelatinase-associated lipocalin (NGAL) (reflecting neutrophil activation); IL-6, IL-8, IL-10, IL-23, IL-27, and IL-1RA (cytokines); sE-selectin, soluble vascular cell adhesion molecule (sVCAM)-1, syndecan, endocan, sTie2, angiopoietin-1, angiopoietin-2, von Willebrand factor, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), s-thrombomodulin, protein C, tissue factor pathway inhibitor (TFPI) and D-dimer (reflecting activation and function of the vascular endothelium and coagulation system). Leukocyte counts and differentials, as well as platelet counts were determined in K2EDTA anticoagulated blood in the institutional routine hematology laboratory. Patient stratification In the primary analysis, patients were stratified using a ferritin level ≥ 500ng/ml as cutoff value, considering that several trials in patients with CAP caused by SARS-CoV2 use this value as inclusion criterion (NCT04530578, NCT04341675, NCT04443881). According to literature routine laboratory hospitals consider ferritin to be elevated when levels are above 200 ng/ml in women and above 300 ng/ml in men [6, 21]. Based hereon we stratified CAP patients in our secondary analysis into those with normal (< 250 ng/ml) and elevated (≥250 ng/ml) plasma ferritin levels. Statistical analysis Statistical analysis was performed in the R statistical framework (Version 3.6.3, R Core Team 2020. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria). All results are presented as numbers (percentages) for categorical variables, median and interquartile ranges (IQR, Q1-Q3) for nonparametric quantitative variables, and mean ± standard deviation of the mean (SD) for parametric quantitative variables. Groups were compared as appropriate: continuous nonparametric data were analysed using a Wilcoxon signed rank sum- or KruskalWallis test; categorical data were analysed using a χ2 or Fisher exact test; continuous parametric data were analysed using a Student t test. Survival curves were compared
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