Summary 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.
Introduction:
Prognosis of Coronavirus disease 2019 (Covid-19) patients with vascular risk factors, and certain comorbidities is worse. The impact of chronic neurological disorders (CND) on prognosis ...is unclear. We evaluated if the presence of CND in Covid-19 patients is a predictor of a higher in-hospital mortality. As secondary endpoints, we analyzed the association between CND, Covid-19 severity, and laboratory abnormalities during admission.
Methods:
Retrospective cohort study that included all the consecutive hospitalized patients with confirmed Covid-19 disease from March 8th to April 11th, 2020. The study setting was Hospital Clínico, tertiary academic hospital from Valladolid. CND was defined as those neurological conditions causing permanent disability. We assessed demography, clinical variables, Covid-19 severity, laboratory parameters and outcome. The primary endpoint was in-hospital all-cause mortality, evaluated by multivariate cox-regression log rank test. We analyzed the association between CND, covid-19 severity and laboratory abnormalities.
Results:
We included 576 patients, 43.3% female, aged 67.2 years in mean. CND were present in 105 (18.3%) patients. Patients with CND were older, more disabled, had more vascular risk factors and comorbidities and fewer clinical symptoms of Covid-19. They presented 1.43 days earlier to the emergency department. Need of ventilation support was similar. Presence of CND was an independent predictor of death (HR 2.129, 95% CI: 1.382–3.280) but not a severer Covid-19 disease (OR: 1.75, 95% CI: 0.970–3.158). Frequency of laboratory abnormalities was similar, except for procalcitonin and INR.
Conclusions:
The presence of CND is an independent predictor of mortality in hospitalized Covid-19 patients. That was not explained neither by a worse immune response to Covid-19 nor by differences in the level of care received by patients with CND.
To evaluate if an intraoperative cerebral regional oxygen saturation (crSO2) decrease, less pronounced than 20% below baseline (the current threshold believed to be associated with cognitive ...dysfunction in adults), is associated with negative postoperative behavioral changes (NPOBC) in the pediatric population after noncardiac surgeries.
A prospective observational study was conducted with 198 children aged 2-12 years old scheduled for noncardiac procedures under general anesthesia. Intraoperatively, crSO2 was monitored with a cerebral oximeter. On postoperative day 7, the Post-Hospital Behavior Questionnaire was used to diagnose NPOBC.
The incidence of NPOBC was 38.8%. Logistic regression analysis revealed that with every 1% reduction of crSO2 from the baseline value, the odds of developing NPOBC were 1.199 higher. Likewise, preoperative anxiety (OR 2.832, P = .006), duration of surgery (OR 1.026, P < .0001), and being between the ages of 2 and 3 years (OR 2.604, P = .048) were associated with NPOBC incidence. The multivariable logistic regression model receiver operating characteristic curve showed an area under the curve (95% CI) = 0.820 (0.759-0.881).
During noncardiac surgeries in the pediatric population, an intraoperative decrease in crSO2 less pronounced than 20% from the baseline value is associated with negative postoperative behavior changes on postoperative day 7. The long-term implications remain to be determined, but this supports attention to crSO2 during noncardiac surgeries.
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 analysisLCN2/HLA-DRA0.90 (0.85–0.96), MMP8/HLA-DRA0.89 (0.84–0.95), procalcitonin0.80 (0.73–0.88) (AUROC, confidence interval 95%), and also in the multivariate analysisLCN2/HLA-DRA8.57 (2.25–32.62); MMP8/HLA-DRA8.03 (2.10–30.76), procalcitonin4.20 (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.
The 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.
We 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.
In-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).
Our 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.
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.
Intravenous immunoglobulins (IVIGs) have not yet demonstrated robust evidence in the benefit for treatment of sepsis. In spite of multiple clinical trials performed with IVIG in sepsis, it remains an ...experimental therapy for this severe condition. Nonetheless, these trials do not address a number of potential confounding factors, concerning both the patient and the IVIG preparations, which could greatly affect the final result. To name a few, endogenous levels of immunoglobulin isotypes and subclasses are not assessed prior to treatment. The presence/absence of patient antibodies against the microorganism(s) causing sepsis is not evaluated. The accuracy of antibiotic prescription is not included as an adjusting variable. The degree of patient immunosuppression (previous or induced by sepsis) is not documented. In turn, the concentration and antimicrobial specificities of the antibodies contained in the batches of IVIG are not assessed. Neither the pharmacokinetics of IVIG nor its potential immunomodulatory effects are evaluated. In addition, the concept of 'window of opportunity' for IVIG administration following diagnosis of sepsis is not considered. In conclusion, addressing these factors could help to individualise treatment with IVIG for sepsis, which could enhance the opportunities of this drug to show benefits in terms of survival in this severe condition.
Boomer et al 5 reported extensive depletion of splenic CD4, CD8, and HLA-DR cells in patients dying of sepsis. ...HLA-DR expression in monocytes has been proposed to be a reliable predictor of ...mortality in severe sepsis 6. Boomer et al 5 reported extensive depletion of splenic CD4, CD8, and HLA-DR cells in patients dying of sepsis. ...HLA-DR expression in monocytes has been proposed to be a reliable predictor of mortality in severe sepsis 6. ...defective expression of genes playing critical roles in T helper/B-cell activation and immunoglobulin isotype switching could contribute to explain the low levels of IgG observed in patients dying of SS.
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