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      Influence of pathogen and focus of infection on procalcitonin values in sepsis patients with bacteremia or candidemia

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          Abstract

          Background

          This study aimed to evaluate the accuracy of procalcitonin (PCT) serum concentrations to diagnose Gram-negative bacteremia and the association of PCT serum concentrations with more specific pathogens and the focus of infection.

          Methods

          Secondary analysis of the prospectively collected patient-level dataset from a cluster randomized quality improvement trial was performed. The trial included sepsis patients with organ dysfunction treated in the participating intensive care units from 2011 to 2015. Test performance for the prediction of Gram-negative bacteremia was assessed by receiver operating curve analysis. Independent effects of specific pathogen groups and foci of infection on PCT concentrations were assessed by linear logistic regression models.

          Results

          Blood cultures (BC) and PCT concentrations had been taken in 4858 of 6561 documented patients. PCT was significantly higher in Gram-negative bacteremia compared to Gram-positive bacteremia or candidemia ( p < 0.001). The area under the curve was 0.72 (95% confidence interval 0.71–0.74) for the prediction of Gram-negative bacteremia compared to all other blood culture results including negative blood cultures. The optimized cutoff value was 10 ng/ml (sensitivity 69%, specificity 35%). PCT differed significantly between specific groups of pathogens ( p < 0.001) with highest concentrations in Escherichia coli, Streptococcus species and other Enterobacteriaceae. PCT was highest in urogenital followed by abdominal infection and lowest in respiratory infection ( p < 0.001). In a linear regression model, Streptococci, E. coli and other Enterobacteriaceae detected from BC were associated with three times higher PCT values. Urogenital or abdominal foci of infection were associated with twofold increased PCT values independent of the pathogen.

          Conclusions

          Serum PCT concentrations are higher in patients with Gram-negative bacteremia than in patients with Gram-positive bacteremia or candidemia. However, the discriminatory power of this difference is too low to guide therapeutic decisions. Variations in PCT serum concentrations are not determined solely by Gram-negative or Gram-positive bacteria but are also affected by distinct groups of pathogens and different foci of infection.

          Trial registration

          ClinicalTrials.gov, NCT01187134. Registered on 23 August 2010.

          Electronic supplementary material

          The online version of this article (10.1186/s13054-018-2050-9) contains supplementary material, which is available to authorized users.

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          Most cited references 29

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          Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells.

           F Re,  J Strominger (2001)
          Toll-like receptors (TLRs) mediate cell activation by various microbial products. Here, we demonstrate that activation of dendritic cells by TLR2 or TLR4 agonists, although it led to comparable activation of NF-kappa B and mitogen-activated protein kinase (MAPK) family members, resulted in striking differences in cytokine and chemokine gene transcription, suggesting that TLR2 and TLR4 signaling is not equivalent. A TLR4 agonist specifically promoted the production of the Th1-inducing cytokine interleukin (IL) 12 p70 and the chemokine interferon-gamma inducible protein (IP)-10, which is also associated to Th1 responses. In contrast, TLR2 stimulation failed to induce IL-12 p70 and interferon-gamma inducible protein (IP)-10 but resulted in the release of the IL-12 inhibitory p40 homodimer, producing conditions that are predicted to favor Th2 development. TLR2 stimulation also resulted in preferential induction of IL-8 and p19/IL-23. Involvement of phosphatidylinositol 3-kinase and p38 MAPK in the TLR-mediated induction of several cytokine and chemokine messages was demonstrated using specific inhibitors. Thus, TLRs can translate the information regarding the nature of pathogens into differences in the cytokines and chemokines produced by dendritic cells and therefore may contribute to the polarization of the acquired immune response.
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            Physiology and genetics of procalcitonin.

            Procalcitonin (PCT), a protein of 116 amino-acids with molecular weight of 13 kDa, was discovered 25 years ago as a prohormone of calcitonin produced by C-cells of the thyroid gland and intracellularly cleaved by proteolytic enzymes into the active hormone. Circulating levels of PCT in healthy subjects are below detection limit. Since 1993 when its elevated level was found in patients with bacterial infection, PCT became an important protein in the detection and differential diagnostics of inflammatory states. The production of PCT during inflammation is linked with a bacterial endotoxin and with inflammatory cytokines (TNF, IL-6). PCT detectable in the plasma during inflammation is not produced in C-cells of the thyroid. The probable site of PCT production during inflammation are the neuroendocrine cells in the lungs or intestine. There is no evidence of plasma PCT binding to cellular receptors of calcitonin, and the role of PCT in calcium and phosphate metabolism during sepsis is still not clear. Other hypothetical roles of PCT (cytokine network regulation, PCT as an endogenous non-steroid antiinflammatory drug) are being considered.
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              Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria.

              Sepsis caused by gram-negative bacteria and that caused by gram-positive bacteria often manifest similar clinical features. We investigated plasma proinflammatory cytokine profiles in patients with sepsis due to gram-positive and gram-negative bacteria and studied the cytokine production and differential gene regulation of leukocytes stimulated ex vivo with Escherichia coli lipopolysaccharide or heat-killed Staphylococcus aureus. Concentrations of tumor necrosis factor alpha, interleukin 1 receptor antagonist (IL-1Ra), IL-8, IL-10, IL-18 binding protein, procalcitonin, and protein C in plasma did not differ between patients with sepsis due to gram-negative and gram-positive bacteria. However, plasma IL-1beta, IL-6, and IL-18 concentrations were significantly higher in patients with sepsis due to gram-positive bacteria. Ex vivo stimulation of whole blood with heat-killed S. aureus markedly increased IL-1beta and IL-18 levels more than E. coli lipopolysaccharide stimulation. Microarray analysis revealed at least 359 cross-validated probe sets (genes) significant at the P < 0.001 level whose expression discriminated among gram-negative-organism-stimulated, gram-positive-organism-stimulated, and unstimulated whole-blood leukocytes. The host inflammatory responses to gram-negative and gram-positive stimuli share some common response elements but also exhibit distinct patterns of cytokine appearance and leukocyte gene expression.
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                Author and article information

                Contributors
                Daniel.thomas@med.uni-jena.de
                poidinger@gmx.at
                matthias.kott@uksh.de
                manfred.weiss@uniklinik-ulm.de
                Konrad.Reinhart@med.uni-jena.de
                Frank.Bloos@med.uni-jena.de
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                13 May 2018
                13 May 2018
                2018
                : 22
                Affiliations
                [1 ]ISNI 0000 0000 8517 6224, GRID grid.275559.9, Center for Sepsis Control and Care, , Jena University Hospital, ; Jena, Germany
                [2 ]ISNI 0000 0000 8517 6224, GRID grid.275559.9, Department of Anesthesiology and Intensive Care Medicine, , Jena University Hospital, ; Am Klinikum 1, 07747 Jena, Germany
                [3 ]ISNI 0000 0004 0646 2097, GRID grid.412468.d, Department of Anaesthesiology and Intensive Care Medicine, , University Hospital Schleswig-Holstein, ; Campus Kiel, Kiel, Germany
                [4 ]GRID grid.410712.1, Clinic of Anaesthesiology, , University Hospital Medical School, ; Ulm, Germany
                Article
                2050
                10.1186/s13054-018-2050-9
                5949148
                29753321
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: FKZ 01EO1002
                Award Recipient :
                Categories
                Research
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                © The Author(s) 2018

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