66 Chapter 4 Baseline characteristics and outcome of CAP patients stratified according to admission plasma ferritin levels ≥500 ng/ml or <500 ng/ml Forty-six CAP patients (26%) had a plasma ferritin concentration of ≥500 ng/ml versus none of the control subjects (Figure 1). CAP patients with plasma ferritin levels ≥500 ng/ml were comparable to CAP patients with plasma ferritin concentrations <500 ng/ml regarding demographics and chronic comorbidities, although in the former group chronic obstructive pulmonary disease (COPD) was less frequent and immunosuppression more frequent (Table 1). Patients with plasma ferritin levels ≥500ng/ml had a higher PSI score than those with plasma ferritin concentrations <500 ng/ml, whilst the MEWS and qSOFA scores were not different between groups. The rate of ICU admission and mortality at day 28 were low and not different between groups. A causative pathogen was detected in 67 of 128 CAP patients (52%) with plasma ferritin levels <500 ng/mL and in 25 of 46 CAP patients (54%) with plasma ferritin levels ≥500 ng/mL (not different between groups; Supplementary Table 1). In both ferritin groups the most common pathogens were Streptococcus pneumoniae, Haemophilus influenzae, Influenza virus A and Influenza virus B. Patients with ferritin levels of ≥500 ng/ml show enhanced systemic inflammatory, cytokine and endothelial-procoagulant responses To obtain insight into the association of plasma ferritin concentrations ≥500 ng/ml with host response aberrations pertaining to pathophysiological pathways implicated in the pathogenesis of pneumonia and sepsis, we compared the plasma values of 26 protein biomarkers reflective of key host response domains between patients with ferritin levels ≥500 ng/ml or <500 ng/ml. Of biomarkers indicative of systemic inflammation, CRP, sCD163, and tenascin-C were higher in patients with admission ferritin levels ≥500 ng/ml whereas sTREM-1 was not (Figure 2). Hyperferritinemia ≥500 ng/ml was associated with higher plasma levels of the neutrophil degranulation products MPO and proteinase-3 (both constituents of azurophilic granules) but not of NGAL (derived from secondary granules) [22]; neutrophil counts were not different between groups (Table 1). Patients with ferritin levels ≥500 ng/ml also showed exaggerated cytokine responses, as reflected by higher plasma levels of IL-8, IL-10, IL-27 and IL-1RA, whilst IL-6 and IL-23 were not different between groups (Figure 3). In addition, patients with ferritin levels ≥500 ng/ml had higher plasma concentrations of biomarkers indicative of endothelial activation (sVCAM-1, von Willebrand factor, s-thrombomodulin, TFPI), glycocalyx integrity (syndecan) and a more disturbed endothelial barrier function (sTie2 and angiopoietin-2); sE-selectin, endocan, ADAMTS13 and angiopoietin-1 did not differ between groups (Figure 4). Admission plasma ferritin ≥500 ng/ml was associated with enhanced activation of the coagulation system, as indicated by higher plasma levels of D-dimer; also, the anticoagulant proteins s-thrombomodulin, protein C and TFPI were higher in this high ferritin group.
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