María Heredia-Rodríguez

Defining immunological dysfunction in sepsis: A requisite tool for precision medicine

OBJECTIVES Immunological dysregulation is now recognised as a major pathogenic event in sepsis. Stimulation of immune response and immuno-modulation are emerging approaches for the treatment of this disease. Defining the underlying immunological alterations in sepsis is important for the design of future therapies with immuno-modulatory drugs. METHODS Clinical studies evaluating the immunological response in adult patients with Sepsis and published in PubMed were reviewed to identify features of immunological dysfunction. For this study we used key words related with innate and adaptive immunity. RESULTS Ten major features of immunological dysfunction (FID) were identified involving quantitative and qualitative alterations of [antigen presentation](FID1), [T and B lymphocytes] (FID2), [natural killer cells] (FID3), [relative increase in T regulatory cells] (FID4), [increased expression of PD-1 and PD-ligand1](FID5), [low levels of immunoglobulins](FID6), [low circulating counts of neutrophils and/or increased immature forms in non survivors](FID7), [hyper-cytokinemia] (FID8), [complement consumption] (FID9), [defective bacterial killing by neutrophil extracellular traps](FID10). CONCLUSIONS This review article identified ten major features associated with immunosuppression and immunological dysregulation in sepsis. Assessment of these features could help in utilizing precision medicine for the treatment of sepsis with immuno-modulatory drugs.

Transcriptomic correlates of organ failure extent in sepsis

OBJECTIVES Sepsis is characterised by the frequent presence of organ failure and marked immunologic alterations. We studied the association between the extent of organ failure and the transcriptomic response of septic patients. METHODS Gene expression profiles in the blood of 74 surgical patients with sepsis were compared with those of 30 surgical patients with no sepsis. Differentially expressed genes were assessed for their correlation with the sequential organ failure (SOFA) score. RESULTS The expression levels of a group of genes participating in the cell cycle (HIST1H1C, CKS2, CCNA2, CDK1, CCNB2, CIT, CCNB1, AURKA, RAD51), neutrophil protease activity (ELANE, ADORA3, MPO, MMP8, CTSG), IL-1R and IL-18R response correlated directly with SOFA and mortality. Genes involved in T cell (LCK, CD3G, CD3D, ZAP70, ICOS, CD3E, CD28, IL2RB, CD8B, CD8A, CD40LG, IL23A, CCL5, SH2D1A, ITK, CD247, TBX21, GATA3, CCR7, LEF1, STAT4) and NK cell immunity (CD244, KLRK1, KLRD1) were inversely associated with SOFA and mortality. CONCLUSIONS The extent of organ failure in sepsis correlates directly with the existence of imbalanced innate and adaptive responses at the transcriptomic level. Quantification of the expression levels of the genes identified here could contribute to the simultaneous assessment of disease severity and immunological alterations in sepsis.

Development of the Post Cardiac Surgery (POCAS) prognostic score

IntroductionThe risk of mortality in cardiac surgery is generally evaluated using preoperative risk-scale models. However, intraoperative factors may change the risk factors of patients, and the organism functionality parameters determined upon ICU admittance could therefore be more relevant in deciding operative mortality. The goals of this study were to find associations between the general parameters of organism functionality upon ICU admission and the operative mortality following cardiac operations, to develop a Post Cardiac Surgery (POCAS) Scale to define operative risk categories and to validate an operative mortality risk score.MethodsWe conducted a prospective study, including 920 patients who had undergone cardiac surgery with cardiopulmonary bypass. Several parameters recorded on their ICU admission were explored, looking for a univariate and multivariate association with in-hospital mortality (90 days). In-hospital mortality was 9%. Four independent factors were included in the POCAS mortality risk model: mean arterial pressure, bicarbonate, lactate and the International Normalized Ratio (INR). The POCAS scale was compared with four other risk scores in the validation series.ResultsIn-hospital mortality (90 days) was 9%. Four independent factors were included in the POCAS mortality risk model: mean arterial pressure, bicarbonate ratio, lactate ratio and the INR. The POCAS scale was compared with four other risk scores in the validation series. Discriminatory power (accuracy) was defined with a receiver-operating characteristics (ROC) analysis. The best accuracy in predicting in-hospital mortality (90 days) was achieved by POCAS. The areas under the ROC curves of the different systems analyzed were 0.890 (POCAS), followed by 0.847 (Simplified Acute Physiology Score (SAP II)), 0.825 (Sepsis-related Organ Failure Assessment (SOFA)), 0.768 (Acute Physiology and Chronic Health Evaluation (APACHE II)), 0.754 (logistic EuroSCORE), 0.714 (standard EuroSCORE) and 0.699 (Age, Creatinine, Ejection Fraction (ACEF) score).ConclusionsOur new system to predict the operative mortality risk of patients undergoing cardiac surgery is better than others used for this purpose (SAP II, SOFA, APACHE II, logistic EuroSCORE, standard EuroSCORE, and ACEF score). Moreover, it is an easy-to-use tool since it only requires four risk factors for its calculation.

Procalcitonin cannot be used as a biomarker of infection in heart surgery patients with acute kidney injury

PURPOSE We intended to assess how acute kidney injuy impacts on procalcitonin levels in cardiac surgery patients, with or without infection, and whether procalcitonin might be used as a biomarker of infection in acute kidney injuy. MATERIAL AND METHODS A case-control study was designed which included patients that had had cardiac surgery between January 2011 and January 2015. Every patient developing severe sepsis or septic shock (n = 122; 5.5%) was enrolled. In addition, consecutive cardiac surgery patients during 2013 developing systemic inflammatory response syndrome (n = 318) were enrolled. Those recruited 440 patients were divided into 2 groups, according to renal function. RESULTS Median procalcitonin levels were significantly higher during the 10 postoperative days in the acute kidney injury patients. Regression analysis showed that postoperatory day, creatinine, white blood cells and infection were significantly (P < .0001) associated to serum procalcitonin level. In patients with creatinine ≥2, median procalcitonin levels were similar in infected and non-infected patients. Only when creatinine was less than 2 mg/L, the median procalcitonin levels were significantly higher in patients with infection, as compared to those with no infection. CONCLUSIONS In acute kidney injuy patients, high procalcitonin levels are a marker of acute kidney injuy but will not be able to differentiate infected from non-infected patients.

Predicting cardiac surgery-associated acute kidney injury: The CRATE score

PURPOSE Acute kidney injury (AKI) is a frequent complication after cardiac surgery and is associated with increased mortality. The aim was to design a nondialytic AKI score in patients with previously normal renal function undergoing cardiac surgery. METHODS Data were collected on 909 patients who underwent cardiac surgery with cardiopulmonary bypass between 2012 and 2014. A total of 810 patients fulfilled the inclusion criteria. Patients were classified as having AKI based on the RIFLE criteria. Postoperative AKI occurred in 137 patients (16.9%). Several parameters were recorded preoperatively, intraoperatively, and at intensive care unit admission, looking for a univariate and multivariate association with AKI risk. A second data set of 741 patients, from 2 different hospitals, was recorded as a validation cohort. RESULTS Four independent risk factors were included in the CRATE score: creatinine (odds ratio [OR], 9.66; 95% confidence interval [CI], 4.77-19.56; P < .001), EuroSCORE (OR, 1.40; CI, 1.29-1.52; P < .001), lactate (OR, 1.03; CI, 1.01-1.04; P < .001), and cardiopulmonary bypass time (OR, 1.01; CI, 1.01-1.02; P < .001). The accuracy of the model was good, with an area under the curve of 0.89 (CI, 0.85-0.92). The CRATE score retained good discrimination in validation cohort, with an area under the curve of 0.81 (95% CI, 0.78-0.85). CONCLUSIONS CRATE score is an accurate and easy to calculate risk score that uses affordable and widely available variables in the routine care surgical patients.

Quantification of Immune Dysregulation by Next-generation Polymerase Chain Reaction to Improve Sepsis Diagnosis in Surgical Patients

Objectives: To quantify immunological dysfunction in surgical patients with presence/absence of sepsis using a droplet digital polymerase chain reaction (ddPCR) transcriptomic analysis. The study also aims to evaluate this approach for improving identification of sepsis in these patients. Background: Immune dysregulation is a central event in sepsis. Quantification of the expression of immunological genes participating in the pathogenesis of sepsis could represent a new avenue to improve its diagnosis. Methods: Expression of 6 neutrophil protease genes (MMP8, OLFM4, LCN2/NGAL, LTF, PRTN3, MPO) and also of 5 genes involved in the immunological synapse (HLA-DRA, CD40LG, CD3E, CD28, ICOS) was quantified in blood from 101 surgical patients with sepsis, 53 uninfected surgical patients, and 16 blood donors by using ddPCR. Areas under receiver operating characteristic curves (AUROC) and multivariate regression analysis were employed to test individual genes and gene ratios to identify sepsis, in comparison with procalcitonin. Results: Sepsis-induced overexpression of neutrophil protease genes and depressed expression of immunological synapse genes. MMP8/HLA-DRA, LCN2/HLA-DRA outperformed procalcitonin in differentiating between patients with sepsis and surgical controls in the AUROC analysis: LCN2/HLA-DRA: 0.90 (0.85–0.96), MMP8/HLA-DRA: 0.89 (0.84–0.95), procalcitonin: 0.80 (0.73–0.88) (AUROC, confidence interval 95%), and also in the multivariate analysis: LCN2/HLA-DRA: 8.57 (2.25–32.62); MMP8/HLA-DRA: 8.03 (2.10–30.76), procalcitonin: 4.20 (1.15–15.43) [odds ratio (confidence interval 95%)]. Gene expression levels of HLA-DRA were an independent marker of hospital mortality. Conclusions: Quantifying the transcriptomic ratios MMP8/HLA-DRA, LCN2/HLA-DRA by ddPCR is a promising approach to improve sepsis diagnosis in surgical patients.

Epidemiological trends of sepsis in the twenty-first century (2000–2013): an analysis of incidence, mortality, and associated costs in Spain

BackgroundSepsis has represented a substantial health care and economic burden worldwide during the previous several decades. Our aim was to analyze the epidemiological trends of hospital admissions, deaths, hospital resource expenditures, and associated costs related to sepsis during the twenty-first century in Spain.MethodsWe performed a retrospective study of all sepsis-related hospitalizations in Spanish public hospitals from 2000 to 2013. Data were obtained from records in the Minimum Basic Data Set. The outcome variables were sepsis, death, length of hospital stay (LOHS), and sepsis-associated costs. The study period was divided into three calendar periods (2000–2004, 2005–2009, and 2010–2013).ResultsOverall, 2,646,445 patients with sepsis were included, 485,685 of whom had died (18.4%). The incidence of sepsis (events per 1000 population) increased from 3.30 (2000–2004) to 4.28 (2005–2009) to 4.45 (2010–2013) (p < 0.001). The mortality rates from sepsis (deaths per 10,000 population) increased from 6.34 (2000–2004) to 7.88 (2005–2009) to 7.89 (2010–2013) (p < 0.001). The case fatality rate (CFR) or proportion of patients with sepsis who died decreased from 19.1% (2000–2004) to 18.4% (2005–2009) to 17.9% (2010–2013) (p < 0.001). The LOHS (days) decreased from 15.9 (2000–2004) to 15.7 (2005–2009) to 14.5 (2010–2013) (p < 0.001). Total and per patient hospital costs increased from 2000 to 2011, and then decreased by the impact of the economic crisis.ConclusionsSepsis has caused an increasing burden in terms of hospital admission, deaths, and costs in the Spanish public health system during the twenty-first century, but the incidence and mortality seemed to stabilize in 2010–2013. Moreover, there was a significant decrease in LOHS in 2010–2013 and a decline in hospital costs after 2011.

Combined quantification of procalcitonin and HLA-DR improves sepsis detection in surgical patients

Early recognition of sepsis is a key factor to improve survival to this disease in surgical patients, since it allows prompt control of the infectious source. Combining pro-inflammatory and immunosupression biomarkers could represent a good strategy to improve sepsis detection. Here we evaluated the combination of procalcitonin (PCT) with gene expression levels of HLA-DRA to detect sepsis in a cohort of 154 surgical patients (101 with sepsis and 53 with no infection). HLA-DRA expression was quantified using droplet digital PCR, a next-generation PCR technology. Area under the receiver operating curve analysis (AUROC) showed that the PCT/HLA-DRA ratio outperformed PCT to detect sepsis (AUROC [CI95%], p): PCT: 0.80 [0.73–0.88], <0.001; PCT/HLA-DRA: 0.85 [0.78–0.91], <0.001. In the multivariate analysis, the ratio showed a superior ability to predict sepsis compared to that of PCT (OR [CI 95%], p): PCT/HLA-DRA: 7.66 [1.82–32.29], 0.006; PCT: 4.21 [1.15–15.43] 0.030. Multivariate analysis was confirmed using a new surgical cohort with 74 sepsis patients and 21 controls: PCT/HLA-DRA: 34.86 [1.22–995.08], 0.038; PCT: 5.52 [0.40–75.78], 0.201. In conclusion, the combination of PCT with HLA-DRA is a promising strategy for improving sepsis detection in surgical patients.

Impact of an ultraviolet air sterilizer on cardiac surgery patients, a randomized clinical trial

BACKGROUND Numerous studies have evaluated the use of ultraviolet-C devices for terminal disinfection in hospitals, however, to date there is little information about the devices final impact on patients. We investigated the effect of an ultraviolet air sterilizer (UVAS) on the clinical outcomes of cardiac surgery patients. MATERIALS AND METHODS This random, prospective and non-interventional study included 1097 adult patients undergoing elective cardiac surgery: 522 stayed in an ICU room with UVAS (Medixair®) and 575 patients ICU room without UVAS and were used as a control. The primary outcome measure was to evaluate the effect of a UVAS on the overall prevalence of nosocomial infections in postoperative cardiac patients in ICUs. RESULTS No significant differences in ventilator-associated pneumonia (4.6% vs. 5.0%, p=0.77) and total infection (14.0% vs. 15.5%, p=0.45) rates were detected in patients with and without the UVAS. The length of stay in the intensive care unit and at the hospital was similar in both groups, UVAS (4.6 (8.2) days and 18.3 (5.5) days) and without UVAS (4.6 (7.3) days and 19.2 (18.6) days). The 30-day in-hospital mortality rate was 5.3%, no significant differences between groups were observed (p=0.053). CONCLUSION Novel ultraviolet-C technology has not been shown to significantly reduce nosocomial infections or mortality rates in cardiac surgery patients.

Evolution of the Incidence, Mortality, and Cost of Infective Endocarditis in Spain Between 1997 and 2014

Department of Anaesthesiology, Hospital Clínico Universitario, Valladolid, Spain; BioCritic. Group for Biomedical Research in Critical Care Medicine, Valladolid, Spain; Department of Cardiac Surgery, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain; Department of Pharmacology, University of Valladolid, Valladolid, Spain; Department of Microbiology, University of Valladolid, Valladolid, Spain; Ministerio de Sanidad, Servicios Sociales e Igualdad, Madrid, Spain.