Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection; no current clinical measure adequately reflects the concept of dysregulated response. Coagulation plays a pivotal role in the normal response to pathogens (immunothrombosis), thus the evolution toward sepsis-induced coagulopathy could be individuate through coagulation/fibrinolysis-related biomarkers. We focused on the role of D-dimer assessed within 24 h after admission in predicting clinical outcomes in a cohort of 270 patients hospitalized in a 79 months period for meningitis and/or bloodstream infections due to Streptococcus pneumoniae (n = 162) or Neisseria meningitidis (n = 108). Comparisons were performed with unpaired t-test, Mann-Whitney-test or chi-squared-test with continuity correction, as appropriate, and multivariable logistic regression analysis was performed with Bayesian model averaging. In-hospital mortality was 14.8% for the overall population, significantly higher in S. pneumoniae than in N. meningitidis patients: 19.1 vs. 8.3%, respectively (p = 0.014). At univariable logistic regression analysis the following variables were significantly associated with in-hospital mortality: pneumococcal etiology, female sex, age, ICU admission, SOFA score, septic shock, MODS, and D-dimer levels. At multivariable analysis D-dimer showed an effect only in N. meningitidis subgroup: as 500 ng/mL of D-dimer increased, the probability of unfavorable outcome increased on average by 4%. Median D-dimer was significantly higher in N. meningitidis than in S. pneumoniae patients (1,314 vs. 1,055 ng/mL, p = 0.009). For N. meningitidis in-hospital mortality was 0% for D-dimer <500 ng/mL, very low (3.5%) for D-dimer <7,000 ng/mL, and increased to 26.1% for D-dimer >7,000 ng/mL. Kaplan-Meier analysis of in-hospital mortality showed for N. meningitidis infections a statistically significant difference for D-dimer >7,000 ng/mL compared to values <500 ng/mL (p = 0.021) and 500–3,000 ng/mL (p = 0.002). For S. pneumoniae the mortality risk resulted always high, over 10%, irrespective by D-dimer values. In conclusion, D-dimer is rapid to be obtained, at low cost and available everywhere, and can help stratify the risk of in-hospital mortality and complications in patients with invasive infections due to N. meningitidis: D-dimer <500 ng/mL excludes any further complications, and a cut-off of 7,000 ng/mL seems able to predict a significantly increased mortality risk from much <10% to over 25%.
Highlights
Sepsis is a heterogeneous syndrome defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, associated with an in-hospital mortality >10% [1, 2]
The aim of this study is to evaluate in a large cohort of patients with meningitis and/or bloodstream infections (BSI) due to S. pneumoniae or N. meningitidis the main clinical and laboratory characteristics and variables associated with in-hospital mortality and complications, with a particular focus on the role of D-dimer as biomarker for early prediction of clinically relevant outcomes
Our results do not confirm the findings of Semeraro et al [6, 7] about a higher mortality for low D-dimer levels, and agree with those of Turak et al [8] and Schwameis et al [9]: we found for N. meningitidis an in-hospital mortality varying from 0% for Ddimer levels
Summary
Sepsis is a heterogeneous syndrome defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, associated with an in-hospital mortality >10% [1, 2]. The role of biomarkers [biological observations that substitute for and ideally predict a clinically relevant endpoint [3]] for diagnostic and prognostic assessment in case of sepsis has been extensively investigated in literature, but to date no current clinical measure seems able to reflect the concept of “dysregulated host response” [1]; identifying a biomarker reflective of host-response interaction would be of great interest It has been known for several years that coagulation plays a pivotal role in the physiological host response to pathogens: immunothrombosis, mediated by immune cells and by specific thrombosis-related molecules, leads to the generation of a localized intravascular scaffold that facilitates the recognition, containment and killing of pathogens, limiting their diffusion through the circulatory system, protecting host integrity and limiting major organ damage [4]: the loss of the physiologically localized activation of coagulation, the signature feature of disseminated intravascular coagulation (DIC), is a hallmark of sepsis and invasive infections [4]. Other studies showed that the mortality is effectively predicted by high levels, with D-dimer ≥4,200 ng/mL effective in identifying the patients with infective endocarditis (IE) [8]
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