Circulating neutrophil counts and mortality in septic shock

Producción CientíficaPolynuclear neutrophils can play dual roles in sepsis: on the one hand they mediate major antimicrobial activities and on the other hand they can contribute to the development of multiple organ failure [1]. Nonetheless, in spite of the importance of these cells in sepsis, the influence of the circulating neutrophil count (CNC) on the prognosis of septic patients with this pathology has not been properly evaluated. We analyzed the association between CNC and outcome in two cohorts of patients with diagnostic criteria of septic shock (SS) [2]: the first was recruited in the context of a single center study (EXPRESS study, discovery cohort, n = 195; Table 1), and the second in the context of a multi-centric study (GRECIA study, validation cohort, n = 194; Table 2). Written informed consent was obtained from each patient or their legal representative. The two studies were approved by the Research Ethics Committee of the Hospital Clínico Universitario, Valladolid, Spain (for the EXPRESS study) and Hospital Universitario Río Hortega, Valladolid, Spain (coordinating center for the GRECIA study).Instituto de Salud Carlos III (grant PI 10/01362)Junta de Castilla y León (grant BOCYL-D-26072010

Early natural killer cell counts in blood predict mortality in severe sepsis

Producción CientíficaIn an attempt to evaluate the quantitative changes in the status of immunocompetence in severe sepsis over time and its potential influence on clinical outcome, we monitored the evolution of immunoglobulins (Igs) (IgG, IgA and IgM), complement factors (C3 and C4) and lymphocyte subsets (CD4+ T cells, CD8+ T cells, B cells (CD19+) and natural killer (NK) cells (CD3-CD16+CD56+)) in the blood of 50 patients with severe sepsis or septic shock at day 1, day 3 and day 10 following admission to the ICU. Twenty-one patients died, ten of whom died within the 72 hours following admission to the ICU. The most frequent cause of death (n = 12) was multiorgan dysfunction syndrome. At day 1, survivors showed significantly higher levels of IgG and C4 than those who ultimately died. On the contrary, NK cell levels were significantly higher in the patients who died. Survivors exhibited a progressive increase from day 1 to day 10 on most of the immunological parameters evaluated (IgG, IgA, IgM, C3, CD4+, CD8+ T cells and NK cells). Multivariate Cox regression analysis, including age, sex, APACHE II score, severe sepsis or septic shock status and each one of the immunological parameters showed that NK cell counts at day 1 were independently associated with increased risk of death at 28 days (hazard ratio = 3.34, 95% CI = 1.29 to 8.64; P = 0.013). Analysis of survival curves provided evidence that levels of NK cells at day 1 (> 83 cells/mm3) were associated with early mortality. Our results demonstrate the prognostic role of NK cells in severe sepsis and provide evidence for a direct association of early counts of these cells in blood with mortality

Critical COPD respiratory illness is linked to increased transcriptomic activity of neutrophil proteases genes

BACKGROUND: Gene expression profiling (GEP) in cells obtained from peripheral blood has shown that this is a very useful approach for biomarker discovery and for studying molecular pathogenesis of prevalent diseases. While there is limited literature available on gene expression markers associated with Chronic Obstructive Pulmonary Disease (COPD), the transcriptomic picture associated with critical respiratory illness in this disease is not known at the present moment. FINDINGS: By using Agilent microarray chips, we have profiled gene expression signatures in the whole blood of 28 COPD patients hospitalized with different degrees of respiratory compromise.12 of them needed of admission to the ICU, whilst 16 were admitted to the Respiratory Medicine Service. GeneSpring GX 11.0 software was used for performing statistical comparisons of transcript levels between ICU and non-ICU patients. Ingenuity pathway analysis 8.5 (IPA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to select, annotate and visualize genes by function and pathway (gene ontology). T-test showed evidence of 1501 genes differentially expressed between ICU and non-ICU patients. IPA and KEGG analysis of the most representative biological functions revealed that ICU patients had increased levels of neutrophil gene transcripts, being [cathepsin G (CTSG)], [elastase, neutrophil expressed (ELANE)], [proteinase 3 (PRTN3)], [myeloperoxidase (MPO)], [cathepsin D (CTSD)], [defensin, alpha 3, neutrophil-specific (DEFA3)], azurocidin 1 (AZU1)], and [bactericidal/permeability-increasing protein (BPI)] the most representative ones. Proteins codified by these genes form part of the azurophilic granules of neutrophils and are involved in both antimicrobial defence and tissue damage. This “neutrophil signature” was paralleled by the necessity of advanced respiratory and vital support, and the presence of bacterial infection. CONCLUSION: Study of transcriptomic signatures in blood suggests an essential role of neutrophil proteases in COPD patients with critical respiratory illness. Measurement and modulation of the expression of these genes could present an option for clinical monitoring and treatment of severe COPD exacerbations

Exercise Ventilatory Inefficiency in Post-COVID-19 Syndrome: Insights from a Prospective Evaluation

The present study was partially granted by Gerencia Regional de Salud de Castilla y León under grant number GRS COVID 111/A/20 and a grant from the Spanish Society of Cardiology SEC/FEC-INVCLI 2.Introduction: Coronavirus disease 2019 (COVID-19) is a systemic disease characterized by a disproportionate inflammatory response in the acute phase. This study sought to identify clinical sequelae and their potential mechanism. Methods: We conducted a prospective single-center study (NCT04689490) of previously hospitalized COVID-19 patients with and without dyspnea during mid-term follow-up. An outpatient group was also evaluated. They underwent serial testing with a cardiopulmonary exercise test (CPET), transthoracic echocardiogram, pulmonary lung test, six-minute walking test, serum biomarker analysis, and quality of life questionaries. Results: Patients with dyspnea (n = 41, 58.6%), compared with asymptomatic patients (n = 29, 41.4%), had a higher proportion of females (73.2 vs. 51.7%; p = 0.065) with comparable age and prevalence of cardiovascular risk factors. There were no significant differences in the transthoracic echocardiogram and pulmonary function test. Patients who complained of persistent dyspnea had a significant decline in predicted peak VO2 consumption (77.8 (64–92.5) vs. 99 (88–105); p 50% of COVID-19 survivors present a symptomatic functional impairment irrespective of age or prior hospitalization. Our findings suggest a potential ventilation/perfusion mismatch or hyperventilation syndrome.Fac. de MedicinaTRUEJunta de Castilla y León. Gerencia Regional de Salud de Castilla y LeónSociedad Española de Cardiologíapu

Assessment of PaO2/FiO2 for stratification of patients with moderate and severe acute respiratory distress syndrome

Objectives: A recent update of the definition of acute respiratory distress syndrome (ARDS) proposed an empirical classification based on ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) at ARDS onset. Since the proposal did not mandate PaO2/FiO2 calculation under standardised ventilator settings (SVS), we hypothesised that a stratification based on baseline PaO2/FiO2 would not provide accurate assessment of lung injury severity. Design: A prospective, multicentre, observational study. Setting: A network of teaching hospitals. Participants: 478 patients with eligible criteria for moderate (100300). Primary and secondary outcomes Group severity and hospital mortality. Results: At ARDS onset, 173 patients had a PaO2/FiO2≤100 but only 38.7% met criteria for severe ARDS at 24 h under SVS. When assessed under SVS, 61.3% of patients with severe ARDS were reclassified as moderate, mild and non-ARDS, while lung severity and hospital mortality changed markedly with every PaO2/FiO2 category (p<0.000001). Our model of risk stratification outperformed the stratification using baseline PaO2/FiO2 and non-standardised PaO2/FiO2 at 24 h, when analysed by the predictive receiver operating characteristic (ROC) curve: area under the ROC curve for stratification at baseline was 0.583 (95% CI 0.525 to 0.636), 0.605 (95% CI 0.552 to 0.658) at 24 h without SVS and 0.693 (95% CI 0.645 to 0.742) at 24 h under SVS (p<0.000001). Conclusions: Our findings support the need for patient assessment under SVS at 24 h after ARDS onset to assess disease severity, and have implications for the diagnosis and management of ARDS patients. Trial registration numbers NCT00435110 and NCT00736892

Endothelial dysfunction is an early indicator of sepsis and neutrophil degranulation of septic shock in surgical patients

Producción CientíficaBackground: Stratification of the severity of infection is currently based on the Sequential Organ Failure Assessment (SOFA) score, which is difficult to calculate outside the ICU. Biomarkers could help to stratify the severity of infection in surgical patients. Methods: Levels of ten biomarkers indicating endothelial dysfunction, 22 indicating emergency granulopoiesis, and six denoting neutrophil degranulation were compared in three groups of patients in the first 12 h after diagnosis at three Spanish hospitals. Results: There were 100 patients with infection, 95 with sepsis and 57 with septic shock. Seven biomarkers indicating endothelial dysfunction (mid-regional proadrenomedullin (MR-ProADM), syndecan 1, thrombomodulin, angiopoietin 2, endothelial cell-specific molecule 1, vascular cell adhesion molecule 1 and E-selectin) had stronger associations with sepsis than infection alone. MR-ProADM had the highest odds ratio (OR) in multivariable analysis (OR 11·53, 95 per cent c.i. 4·15 to 32·08; P = 0·006) and the best area under the curve (AUC) for detecting sepsis (0·86, 95 per cent c.i. 0·80 to 0·91; P < 0·001). In a comparison of sepsis with septic shock, two biomarkers of neutrophil degranulation, proteinase 3 (OR 8·09, 1·34 to 48·91; P = 0·028) and lipocalin 2 (OR 6·62, 2·47 to 17·77; P = 0·002), had the strongest association with septic shock, but lipocalin 2 exhibited the highest AUC (0·81, 0·73 to 0·90; P < 0·001). Conclusion: MR-ProADM and lipocalin 2 could be alternatives to the SOFA score in the detection of sepsis and septic shock respectively in surgical patients with infection.Instituto de Salud Carlos III (grants PI15/01959, PI15/01451 and PI16/01156

Composed endotypes to guide antibiotic discontinuation in sepsis

Abstract Overuse of empiric antibiotic therapy in the ICU is responsible for promoting the dissemination of multidrug-resistant (MDR) bacteria. Shortened antibiotic treatment duration could contribute to palliating the emergence of MDR. Uncertainty about patient evolution is a major concern for deciding to stop antibiotics. Biomarkers could represent a complementary tool to identify those patients for whom antibiotic treatment could be safely discontinued. The biomarker most extensively studied to guide antibiotic withdrawal is procalcitonin (PCT), but its real impact on decreasing the duration of antibiotic treatment is a matter of controversy. Combining biomarkers to rule out complicated outcomes in sepsis patients could represent a better option. Some candidate biomarkers, including mid-regional proadrenomedullin, the percentage of human leukocyte antigen DR (HLA-DR)-positive monocytes, means of fluorescence intensities of HLA-DR on monocytes, interleukin-7 receptor expression levels, immunoglobulin M levels in the serum or the absence of increased proteolysis, have already demonstrated the potential to exclude the risk of progression to septic shock, nosocomial infections, and mortality when tested along the sepsis course. Other promising biomarkers to rule out complicated outcomes are neutrophil protease activity, the adaptive/coagulopathic signatures identified by whole transcriptome analysis by Sweeney et al., and the SRS1 signature identified by Davenport et al. In conclusion, there are a number of promising biomarkers involved in proteolytic, vascular, immunological, and coagulation alterations that could be useful to build composed endotypes to predict uncomplicated outcomes in sepsis. These endotypes could help to identify patients deserving the discontinuation of antibiotics

Eosinophil as a Protective Cell in S. aureus Ventilator-Associated Pneumonia

Cell counts of leukocytes subpopulations are demonstrating to have an important value in predicting outcome in severe infections. We evaluated here the render of leukogram counts to predict outcome in patients with ventilator-associated pneumonia (VAP) caused by Staphylococcus aureus. Data from patients admitted to the ICU of Hospital Clínico Universitario de Valladolid from 2006 to 2011 with diagnosis of VAP caused by S. aureus were retrospectively collected for the study (n=44). Leukocyte counts were collected at ICU admission and also at VAP diagnosis. Our results showed that nonsurvivors had significant lower eosinophil counts at VAP diagnosis. Multivariate Cox regression analysis performed by the Wald test for forward selection showed that eosinophil increments from ICU admission to VAP diagnosis and total eosinophil counts at VAP diagnosis were protective factors against mortality in the first 28 days following diagnosis: (HR [CI 95%], P): (0.996 [0.993–0.999], 0.010); (0.370 [0.180–0.750], 0.006). Patients with eosinophil counts <30 cells/mm3 at diagnosis died earlier. Eosinophil counts identified survivors: (AUROC [CI 95%], P): (0.701 [0.519–0.882], 0.042). Eosinophil behaves as a protective cell in patients with VAP caused by S. aureus

Immunological monitoring to prevent and treat sepsis

The clinical, human and economic burden associated with sepsis is huge. Initiatives such as the Surviving Sepsis Campaign aim to effectively reduce risk of death from severe sepsis and septic shock. Nonetheless, although substantial benefits raised from the implementation of this campaign have been obtained, much work remains if we are to realise the full potential promised by this strategy. A deeper understanding of the processes leading to sepsis is necessary before we can design an effective suite of interventions. Dysregulation of the immune response to infection is acknowledged to contribute to the pathogenesis of the disease. Production of both proinflammatory and immunosuppressive cytokines is observed from the very first hours following diagnosis. In addition, hypogammaglobulinemia is often present in patients with septic shock. Moreover, levels of IgG, IgM and IgA at diagnosis correlate directly with survival. In turn, nonsurvivors have lower levels of C4 (a protein of the complement system) than the survivors. Natural killer cell counts and function also seem to have an important role in this disease. HLA-DR in the surface of monocytes and counts of CD4(+)CD25(+ )T-regulatory cells in blood could also be useful biomarkers for sepsis. At the genomic level, repression of networks corresponding to major histocompatibility complex antigen presentation is observed in septic shock. In consequence, cumulative evidence supports the potential role of immunological monitoring to guide measures to prevent or treat sepsis in a personalised and timely manner (early antibiotic administration, immunoglobulin replacement, immunomodulation). In conclusion, although diffuse and limited, current available information supports the development of large comprehensive studies aimed to urgently evaluate immunological monitoring as a tool to prevent sepsis, guide its treatment and, as a consequence, diminish the morbidity and mortality associated with this severe condition