Septic Blood Research Articles

Clinical features and death risk factors of pneumocystis jirovecii pneumonia in kidney disease patients with immunosuppressive therapy

To investigate the clinical features and death risk factors of pneumocystis jirovecii pneumonia (PJP) in kidney disease patients with immunosuppressive patients. A Retrospective case series study was performed in 52 PJP patients with kidney disease who received immunosuppressive therapy in Nephrology or Respiratory department of Peking University First Hospital from January 1, 2006 to August 31, 2021. Patients were divided into survival group (36 cases) and death group (16 cases) according to their clinical outcomes. Univariate analysis was performed to compare the differences of clinical features between the two groups. Multivariate logistic regression model was used to analyze the death risk factors. The results showed that the median serum creatinine was 192.5 (109.8, 293.7) μmol/L, and the incidence of acute kidney injury was 63.5% (33/52). Univariate analysis showed that age (t=1.197,P=0.030), C-reactive protein level (t=2.378,P=0.022), time from onset to diagnosis (χ2=6.62,P=0.010), PJP severity (χ2=5.482,P=0.019), complicated with septic shock (χ2=3.997,P=0.046), mechanical ventilation (χ2=11.755,P=0.001), and blood purification therapy (χ2=4.748,P=0.029) were statistically significant. There were no statistically significant differences between the two groups in gender, duration and dosage of hormone therapy before PJP onset, intravenous methylprednisolone pulse therapy, immunosuppressant use, and serum creatinine level before and after hospitalization for anti-PJP treatment (all P>0.05). Multivariate analysis showed that the time from onset to diagnosis of PJP was >10 days (OR=40.945, 95%CI: 1.738-451.214; P=0.021) and severe PJP (OR=25.502, 95%CI: 1.426-74.806; P=0.028) was an independent death risk factor for kidney disease complicated with PJP of immunosuppressive therapy. In conclusion, the time from onset to diagnosis of PJP and PJP severity are independent death risk factors in patients with kidney disease complicated with PJP of immunosuppressive therapy. Close attention should be paid to oxygenation condition and early diagnosis can prevent the aggravation of PJP and improve the prognosis.

Identification of ferroptosis-related key genes associated with immune infiltration in sepsis by bioinformatics analysis and in vivo validation

ObjectivesSepsis is a life-threatening infectious disease in which an immune inflammatory response is triggered. The potential effect of ferroptosis-related genes (FRGs) in inflammation of sepsis remained unclear. We focused on identifying and validating core FRGs and their association with immune infiltration in blood from currently all patients with sepsis. MethodsAll current raw data of septic blood were obtained from Gene Expression Omnibus. After removing the batch effect merging into a complete dataset and obtaining Diferentially expressed genes (DEGs). Common cross-talk genes were identified from DEGs and FRGs. WGCNA, GO, KEGG, PPI, GESA, ROC curves, and LASSO regression analysis were performed to indentify and validate key genes based on external septic datasets. Infiltrated immune cells in 2 hub genes (MAPK14 and ACSL4) were conducted using CIBERSORT algorithm and Spearman correlation analysis. Further, the expressions of 2 core FRGs were verified in the LPS-induced ALI and cardiac injury sepsis mice. ResultsMAPK14 and ACSL4 were identified, mostly enriched in T cell infiltration through NOD-like receptor signaling pathway according to the high or low 2 hub genes expression. The upregulated 2 ferroptosis-related genes were validated in LPS-induced ALI and cardiac injury mice, accompanied by upregulation of the NLRP3 pathway. ConclusionMAPK14 and ACSL4 could become robustly reliable and promising biomarkers for sepsis by regulating ferroptosis through the NLRP3 pathway, which is mainly associated with T-cell infiltration.

Rational design of hemocompatible hydrogel microspheres towards pathogen-associated molecular patterns removal for Gram-positive bacteria-induced sepsis

Gram-positive bacterial infection towards sepsis is often difficult to treat due to the various virulence factors such as pore-forming toxins and the corresponding complex pathogenic mechanism. While the currently reported nanoparticles for eliminating toxins are difficult to be used for hemoperfusion due to the nanoscale size, the complex preparation process and poor hemocompatibility. Herein, we design poly (sulfobetaine methacrylate-co-diallyldimethylammonium)/red blood cell membrane (PSDR) hydrogel microspheres via precipitated droplets in-situ cross-linking polymerization as hemoperfusion adsorbents to attract bacteria and adsorb the released toxins simultaneously, providing a deep treatment of sepsis caused by Gram-positive bacteria through blood purification. The PSDR microspheres show excellent and rapid adsorption of bacterial toxins in the simulated perfusion with a 75.6 % removal efficiency in 10 min. Besides, the PSDR microspheres can prevent the cells in septic blood from destroying and activating by bacterial toxins. The rational design of PSDR hydrogel microspheres is expected to provide new solutions for the deep treatment of bacteria-induced sepsis.

Prognostic gene landscapes and therapeutic insights in sepsis-induced coagulopathy

BackgroundSepsis is a common and critical condition encountered in clinical practice that can lead to multi-organ dysfunction. Sepsis-induced coagulopathy (SIC) significantly affects patient outcomes. However, the precise mechanisms remain unclear, making the identification of effective prognostic and therapeutic targets imperative. MethodsThe analysis of transcriptome data from the whole blood of sepsis patients, facilitated the identification of key genes implicated in coagulation. Then we developed a prognostic model and a nomogram to predict patient survival. Consensus clustering classified sepsis patients into three subgroups for comparative analysis of immune function and immune cell infiltration. Single-cell sequencing elucidated alterations in intercellular communication between platelets and immune cells in sepsis, as well as the role of the coagulation-related gene FYN. Real-time quantitative PCR determined the mRNA levels of critical coagulation genes in septic rats' blood. Finally, administration of a FYN agonist to septic rats was observed for its effects on coagulation functions and survival. ResultsThis study identified four pivotal genes—CFD, FYN, ITGAM, and VSIG4—as significant predictors of survival in patients with sepsis. Among them, CFD, FYN, and ITGAM were underexpressed, while VSIG4 was upregulated in patients with sepsis. Moreover, a nomogram that incorporates the coagulation-related genes (CoRGs) risk score with clinical features of patients accurately predicted survival probabilities. Subgroup analysis of CoRGs expression delineated three molecular sepsis subtypes, each with distinct prognoses and immune profiles. Single-cell sequencing shed light on heightened communication between platelets and monocytes, T cells, and plasmacytoid dendritic cells, alongside reduced interactions with neutrophils in sepsis. The collagen signaling pathway was found to be essential in this dynamic. FYN may affect platelet function by modulating factors such as ELF1, PTCRA, and RASGRP2. The administration of the FYN agonist can effectively improve coagulation dysfunction and survival in septic rats. ConclusionsThe research identifies CoRGs as crucial prognostic markers for sepsis, highlighting the FYN gene's central role in coagulation disorders associated with the condition and suggesting novel therapeutic intervention strategies.

Assessment of working conditions and features of respiratory disorders in modern refractory manufacturing

Introduction. Broad prospects for development of refractory manufacturing in Russia necessitate studies of the work environment, especially of the indoor air quality, and respiratory health effects of adverse occupational factors. 
 The purpose of our study was to conduct a general hygienic assessment of working conditions of the core personnel engaged in contemporary refractory manufacturing for more than 10 years and establish their respiratory functional status.
 Materials and methods. We assessed working conditions of press operators of a Ural refractory manufacturing plant in compliance with Russian Guidelines 
 R 2.2.2006–05. The respiratory functional status was established by the results of clinical instrumental testing of refractory production workers who were examined and/or treated at the occupational health clinic of the Yekaterinburg Medical Research Center for Prophylaxis and Health Protection in Industrial Workers 
 in 2015–2021.
 Results. We gave a general assessment of working conditions of press operators engaged in the production of spinel periclase-carbon and fireclay-dinas molded refractories in the first refractory workshop, aluminosilicate refractories at the molding site, and corundum-graphite products in the second refractory workshop. 
 We analyzed the results of instrumental testing and established characteristics of clinical disorders of the respiratory system.
 Limitations. The study has regional (Sverdlovsk Region) and occupational (workers of a refractory manufacturing plant) limitations.
 Conclusion. Occupational risk factors for refractory production workers include silica-containing aerosols, which levels exceed maximum allowable concentrations (Class 3.1), aerosols of disintegration of aluminum oxides (in refractory workshop No. 2), iron in concentrations below MACs (Class 2), higher concentrations of volatile products of phenol formaldehyde resins (Class 3.1 in terms of phenol and up to 3.4 in terms of formaldehyde), increased noise levels for all jobs (Class 3.2), and heavy physical labour (Classes 3.1–3.3). Features of clinical respiratory disorders in the core personnel (press operators) were scarcity of complaints and physical data, absence of pronounced coniotic (respirable dust-related) X-ray findings and inflammatory (septic and allergic) blood changes. Moderate obstructive airway disorders were observed in 30 % of the examined cases.

Uncovering hub genes in sepsis through bioinformatics analysis.

In-depth studies on the mechanisms of pathogenesis of sepsis and diagnostic biomarkers in the early stages may be the key to developing individualized and effective treatment strategies. This study aimed to identify sepsis-related hub genes and evaluate their diagnostic reliability. The gene expression profiles of GSE4607 and GSE131761 were obtained from the Gene Expression Omnibus. Differentially co-expressed genes between the sepsis and control groups were screened. Single-sample gene set enrichment analysis and gene set variation analysis were performed to investigate the biological functions of the hub genes. A receiver operating characteristic curve was used to evaluate diagnostic value. Datasets GSE154918 and GSE185263 were used as external validation datasets to verify the reliability of the hub genes. Four differentially co-expressed genes, FAM89A, FFAR3, G0S2, and FGF13, were extracted using a weighted gene co-expression network analysis and differential gene expression analysis methods. These 4 genes were upregulated in the sepsis group and were distinct from those in the controls. Moreover, the receiver operating characteristic curves of the 4 genes exhibited considerable diagnostic value in discriminating septic blood samples from those of the non-septic control group. The reliability and consistency of these 4 genes were externally validated. Single-sample gene set enrichment analysis and gene set variation analysis analyses indicated that the 4 hub genes were significantly correlated with the regulation of immunity and metabolism in sepsis. The identified FAM89A, FFAR3, G0S2, and FGF13 genes may help elucidate the molecular mechanisms underlying sepsis and drive the introduction of new biomarkers to advance diagnosis and treatment.

Stewardship-Guided T2Candida Testing Shortens Time to Antifungal Treatment and Reduces Antifungal Usage Among Medical Intensive Care Unit Patients With Septic Shock.

Diagnosis of invasive candidiasis (IC) is limited by insensitivity and slow turnaround of cultures. Our objectives were to define the performance of T2Candida, a nonculture test, under guidance of a diagnostic stewardship program, and evaluate impact on time to antifungal initiation and antifungal utilization. This was a retrospective study of adult medical intensive care unit (MICU) patients with septic shock for whom T2Candida testing was performed from March 2017 to March 2020. Patients with positive T2Candida results during this period were compared to MICU patients who did not undergo T2Candida testing but had septic shock and blood cultures positive for Candida from January 2016 through March 2020. Overall, 155 T2Candida tests from 143 patients were included. Nine percent of T2Candida tests were positive compared to 4.5% of blood cultures. Sensitivity, specificity, positive predictive value, and negative predictive value of T2Candida for proven and probable IC were 78%, 95%, 50%, and 99%, respectively. Patients who tested positive for T2Candida (n = 14) were diagnosed earlier and initiated on antifungal therapy sooner than patients with IC (n = 14) diagnosed by blood culture alone (median, 5.6 vs 60 hours; P < .0001). Median antifungal days of therapy/1000 patient-days were 23.3/month preimplementation and 15/month postimplementation (P = .007). Following a negative T2Candida result, empiric antifungals were either not administered in 58% or discontinued within 72 hours in 96% of patients. Diagnostic stewardship guided T2Candida testing resulted in reduced time to IC diagnosis, faster initiation of antifungal therapy, and lower antifungal usage among MICU patients with septic shock.

Histidine-inspired polyacrylonitrile-based adsorbent with excellent hemocompatibility for the simultaneous removal of bacteria and endotoxin in septic blood

Endotoxins (LPS) are components of the cell wall of Gram-negative bacteria that are released when bacterial cell membrane is destroyed, the bacteria and the released LPS have led to serious diseases such as sepsis and septic shock. Histidine functionalized adsorbents have been used to remove LPS, however, the present hemoperfusion adsorbents have drawbacks such as inadequate LPS adsorption capability, high cost of raw material, and so on. Inspired by the structure of histidine and incorporated antibacterial molecules, we synthesize allylamine-modified polyacrylonitrile (PAD)/poly (imidazolium bromide) (PMIBr) composite (PAI) microspheres as hemoperfusion adsorbents. The PAI microspheres show excellent antibacterial ability with high killing efficiency of 98.8% against S. aureus and 95.4% against E. coli. In addition, the adsorption capacity of the microspheres for LPS in PBS is 433.5 EU/g within 3 h, and the LPS concentration could also be reduced from 7.34 EU/mL to below 0.5 EU/mL in the plasma environment. The PAI microspheres exhibit outstanding blood compatibility, antibacterial property and endotoxin removal capability, which have great potential in the treatment of sepsis patients.

Comparative analyses of monocyte memory dynamics from mice to humans.

Innate monocytes can adopt dynamic "memory" states ranging from low-grade inflammation to pathogenic exhaustion, dependent upon signal strength and history of challenges. Low-grade inflammatory monocytes facilitate the pathogenesis of chronic inflammatory diseases, while exhausted monocytes drive the pathogenesis of severe sepsis. Although clinical and basic studies suggest the conservation of key features of exhausted monocytes from human and murine sepsis, systems analyses of monocyte exhaustion among human and murine monocytes are lacking. We performed cross examination of septic monocytes scRNAseq data recently collected from human sepsis patients as well as experimental septic mice, in reference to monocytes experimentally exhausted in vitro. Furthermore, we performed pseudo-time analyses of in vitro programmed monocytes following prolonged challenges causing either low-grade inflammation or exhaustion. Additional comparative analyses of low-grade inflammatory monocytes were performed with scRNAseq data from selected human patients with chronic low-grade inflammatory diseases. Our systems analyses reveal key features of monocyte exhaustion including reduced differentiation, pathogenic inflammation and immune suppression that are highly conserved in human and murine septic monocytes, and captured by in vitro experimental exhaustion. Pseudo-time analyses reveal that monocytes initially transition into a less-differentiated state with proliferative potential. The expansion of proliferative monocytes can be observed not only in experimentally challenged monocytes, but also in tissues of murine sepsis and human septic blood. We observed that monocytes similarly transition into the less-differentiated state when challenged with a subclinical dose endotoxin under chronic inflammatory conditions. Instead of being exhausted, monocytes with prolonged challenges with super-low dose endotoxin bifurcate into the low-grade inflammatory immune-enhancing or the chemotactic/adhesive state, often see in atherosclerosis or auto-immune diseases. Key features of monocyte memory dynamics are identified and conserved in human and murine monocytes, which can be captured by prolonged challenges of innate signals with varying signal strength.

Protective effect of the novel cyclic peptide ASK0912 on mice with sepsis induced by Acinetobacter baumannii

BackgroundSepsis has become a global health concern owing to its increasing incidence and high mortality rate. In the present study, we investigated a novel drug candidate ASK0912 on its protective effects in mice with Acinetobacter baumannii 20–1-induced sepsis, and studied the related mechanisms. Material and methodsTo analyze the protective effect of ASK0912 on septic mice, survival rates, body temperature, organ and blood bacterial loads, white blood cell and platelet counts, organ damage, and cytokine levels were determined. ResultsASK0912 remarkably increased the survival rate of mice with sepsis induced by A. baumannii 20–1 at a low dose of 0.6 mg/kg. Rectal temperature measurements showed that ASK0912 treatment prevented the body temperature decrease of septic mice to some extent. Treatment with ASK0912 can notably reduce the organ and blood bacterial loads and alleviate platelet count reduction due to sepsis. ASK0912 attenuated organ damage, including reduced levels of total bile acids, urea, and creatinine, aggregation of inflammatory cells, and mitigation of structural changes in septic mice, as demonstrated by biochemical analysis and hematoxylin & eosin staining. Additionally, multiplex assay showed that abnormally increased cytokine levels (IL-1β, IL-3, IL-5, IL-6, IL-10, IL-13, MCP-1, RANTES, KC, MIP-1α, MIP-1β, and G-CSF) in septic mice decreased after ASK0912 treatment. ConclusionsASK0912 can not only improve the survival rate, hypothermia, lower the bacterial loads in the organs and blood, but also alleviate the pathophysiological manifestations such as intravascular coagulation abnormalities, organ damages, and immune system disorder of sepsis mice induced by A. baumannii 20–1.

Elevated Urinary Hepcidin Level and Hypoferremia in Infants with Febrile Urinary Tract Infection: A Prospective Cohort Study.

To evaluate the kinetics of serum and urinary hepcidin levels along with anemia-related parameters during the infection course of infants with febrile urinary tract infection (UTI), we enrolled febrile infants aged one to four months in this prospective study. Febrile patients with UTI were allocated into Escherichia coli (E. coli) or non-E. coli groups according to urine culture results. Septic workup, blood hepcidin, iron profile, urinalysis, and urinary hepcidin-creatinine ratio were collected upon admission and 3 days after antibiotic treatment. In total, 118 infants were included. On admission, the febrile UTI group showed a significant reduction in serum iron level and a significant elevation of urinary hepcidin-creatinine ratio compared to the febrile control counterpart. Moreover, urinary hepcidin-creatinine ratio had the highest odds ratio, 2.01, in logistics regression analysis. After 3 days of antibiotic treatment, hemoglobin and the urinary hepcidin-creatinine ratio were significantly decreased. Patients with an E. coli UTI had a significantly decreased urinary hepcidin-creatinine ratio after 3 days of antibiotics treatment, whereas the non-E. coli group showed insignificant changes. Our study suggested that the urinary hepcidin-creatinine ratio elevated during acute febrile urinary tract infection and significantly decreased after 3 days of antibiotics treatment, especially in E. coli UTI.

SCREENING OF POTENTIAL CORE GENES IN THE PERIPHERAL BLOOD OF ADULT PATIENTS WITH SEPSIS BASED ON IMMUNOREGULATION AND SIGNAL TRANSDUCTION FUNCTIONS.

Objective: Based on the functions of immunoregulation and signal transduction, septic peripheral blood sequencing and bioinformatics technology were used to screen potential core targets. Methods: Peripheral blood of 23 patients with sepsis and 10 normal volunteers underwent RNA-seq processing within 24 hours after admission to the hospital. Data quality control and differential gene screening were performed based on R language ( P < 0.01; log2FC ≥ 2). Gene function enrichment analysis was conducted on differentially expressed genes (DEGs). Then, target genes were submitted to STRING to constitute the PPI network, and GSE65682 were used to explore the prognostic relevance of potential core genes. Meta-analysis was used to verify the expression trends of core genes in the sepsis group. Then, cell line localization analysis of core genes in the 5 peripheral blood mononuclear cell samples (normal control = 2; systemic inflammatory response syndrome = 1; SEPSIS = 2) was performed. Results: A total of 1,128 DEGs were obtained between sepsis and normal group, of which 721 were upregulated and 407 downregulated. These DEGs were mainly enriched in leukocyte-mediated cytotoxicity, cell killing regulation, adaptive immune response regulation, lymphocyte-mediated immune regulation, and negative regulation of adaptive immune response. PPI network analysis results showed that CD160, KLRG1, S1PR5, and RGS16 were located in the core area, which are related to adaptive immune regulation, signal transduction, and intracellular components. The above four genes in the core area were found to be related to the prognosis of patients with sepsis, of which RGS16 was negatively correlated with the survival rate, and CD160, KLRG1, and S1PR5 were positively correlated. However, several public data sets showed that CD160, KLRG1, and S1PR5 were all downregulated in the peripheral blood of patients with sepsis, while RGS16 was upregulated in the sepsis group. Single-cell sequencing analysis showed that they were mainly expressed in NK-T cells. Conclusions: CD160, KLRG1, S1PR5, and RGS16 were mainly located in human peripheral blood NK-T cells. Sepsis participants expressed lower levels of S1PR5, CD160, and KLRG1, while sepsis participants expressed higher levels of RGS16. This suggests that they may be potential research targets for sepsis.

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Uridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism of uridine in ferroptosis. The Gene Expression Omnibus (GEO) datasets including lung tissues in lipopolysaccharides (LPS) -induced ALI model or human blood sample of sepsis were collected. In vivo and vitro, LPS was injected into mice or administered to THP-1 cells to generate sepsis or inflammatory models. We identified that uridine phosphorylase 1 (UPP1) was upregulated in lung tissues and septic blood samples and uridine significantly alleviated lung injury, inflammation, tissue iron level and lipid peroxidation. Nonetheless, the expression of ferroptosis biomarkers, including SLC7A11, GPX4 and HO-1, were upregulated, while lipid synthesis gene (ACSL4) expression was greatly restricted by uridine supplementation. Moreover, pretreatment of ferroptosis inducer (Erastin or Era) weakened while inhibitor (Ferrostatin-1 or Fer-1) strengthened the protective effects of uridine. Mechanistically, uridine inhibited macrophage ferroptosis by activating Nrf2 signaling pathway. In conclusion, uridine metabolism dysregulation is a novel accelerator for sepsis-induced ALI and uridine supplementation may offer a potential avenue for ameliorating sepsis-induced ALI by suppressing ferroptosis.

Identification of iron metabolism-related genes in the circulation and myocardium of patients with sepsis via applied bioinformatics analysis.

Early diagnosis of septic cardiomyopathy is essential to reduce the mortality rate of sepsis. Previous studies indicated that iron metabolism plays a vital role in sepsis-induced cardiomyopathy. Here, we aimed to identify shared iron metabolism-related genes (IMRGs) in the myocardium and blood monocytes of patients with sepsis and to determine their prognostic signature. First, an applied bioinformatics-based analysis was conducted to identify shared IMRGs differentially expressed in the myocardium and peripheral blood monocytes of patients with sepsis. Second, Cytoscape was used to construct a protein-protein interaction network, and immune infiltration of the septic myocardium was assessed using single-sample gene set enrichment analysis. In addition, a prognostic prediction model for IMRGs was established by Cox regression analysis. Finally, the expression of key mRNAs in the myocardium of mice with sepsis was verified using quantitative polymerase chain reaction analysis. We screened common differentially expressed genes in septic myocardium and blood monocytes and identified 14 that were related to iron metabolism. We found that HBB, SLC25A37, SLC11A1, and HMOX1 strongly correlated with monocytes and neutrophils, whereas HMOX1 and SLC11A1 strongly correlated with macrophages. We then established a prognostic model (HIF1A and SLC25A37) using the common differentially expressed IMRGs. The prognostic model we established was expected to better aid in diagnosing septic cardiomyopathy. Moreover, we verified these genes using datasets and experiments and found a significant difference between the sepsis and control groups. Common differential expression of IMRGs was identified in blood monocytes and myocardium between sepsis and control groups, among which HIF1A and SLC25A37 might predict prognosis in septic cardiomyopathy. The study may help us deeply understand the molecular mechanisms of iron metabolism and aid in the diagnosis and treatment of septic cardiomyopathy.

Therapeutic Potential of Dopamine and Related Drugs as Anti-Inflammatories and Antioxidants in Neuronal and Non-Neuronal Pathologies

To compile the mechanism of action of DA and the main dopaminergic drugs and show the findings that support the therapeutic potential of these molecules for the treatment of neurological and non-neurological diseases considering their antioxidant and anti-inflammatory actions. We performed a review article. An exhaustive search for information was carried out in specialized databases such as PubMed, PubChem, ProQuest, EBSCO, Scopus, Science Direct, Web of Science, Bookshelf, DrugBank, Livertox, and Clinical Trials. We showed that DA and dopaminergic drugs have emerged for the management of neuronal and nonneuronal diseases with important therapeutic potential as anti-inflammatories and antioxidants. DA and DA derivatives can be an attractive treatment strategy and a promising approach to slowing the progression of disorders through repositioning.

Association between septic patient mortality and blood survivin concentrations

Survivin is a member of inhibitors of apoptosis proteins family. There are not data about the association between mortality of septic patients and blood survivin concentrations. Therefore, the objective of this study was to determine whether exist that association. Observational and prospective study. Three Spanish Intensive Care Units. Patients with sepsis or septic shock according to Sepsis-3 Consensus criteria. Serum survivin concentrations were determined at moment of sepsis diagnosis. Mortality at 30 days. A total of 204 patients were included in the study, of which 75 (36.8%) died in the first 30 days. Lower age ( p < 0.001), serum lactic acid levels ( p = 0.001), rate of septic shock ( p = 0.001) and SOFA ( p < 0.001), and higher serum survivin levels ( p = 0.001) exhibited surviving ( n = 129) than non-surviving patients ( n = 75). We found in multiple logistic regression analysis an association between serum survivin concentrations and mortality independently of SOFA, lactic acid, age, INR, activated partial thromboplastin time (aPTT) and empiric antimicrobial treatment adequate (OR = 0.968; 95% CI = 0.946–0.990; p = 0.005), and also independently of APACHE-II, lactic acid, platelet, INR, aPTT and empiric antimicrobial treatment adequate (OR = 0.966; 95% CI = 0.943–0.989; p = 0.004). There is an association between septic patient mortality and low blood survivin concentrations. Survivina es un miembro de la familia de proteínas inhibidoras de apoptosis. No existen datos sobre la asociación entre la mortalidad de los pacientes sépticos y las concentraciones de survivina en sangre. Por tanto, el objetivo de este estudio fue determinar si existe esa asociación. Estudio observacional y prospectivo. Tres Unidades de Cuidados Intensivos españolas. Pacientes con sepsis o shock séptico según criterios del Consenso Sepsis-3. Se determinaron las concentraciones séricas de survivina en el momento del diagnóstico de la sepsis. Mortalidad a los 30 días. Un total de 204 pacientes se incluyeron en el estudio, 75 (36,8%) de los cuales fallecieron en los primeros 30 días. Menor edad (p < 0,001), niveles séricos de ácido láctico (p = 0,001), tasa de shock séptico (p = 0,001) y SOFA (p < 0,001), y mayores niveles de survivina en suero (p = 0,001) exhibieron los pacientes supervivientes (n = 129) en comparación con los fallecidos (n = 75). El análisis de regresión logística múltiple mostró una asociación entre las concentraciones séricas de survivina y la mortalidad independientemente del SOFA, ácido láctico, edad, INR, tiempo de tromboplastina parcial activada (aPTT) y tratamiento antimicrobiano empírico adecuado (OR = 0,968; IC 95% = 0,946-0,990; p = 0,005), y también independientemente del APACHE-II, ácido láctico, plaquetas, INR, aPTT y tratamiento antimicrobiano empírico adecuado (OR = 0,966; IC 95% = 0,943-0,989; p = 0,004). Existe una asociación entre la mortalidad de los pacientes sépticos y las concentraciones bajas de survivina en sangre.

Association between septic patient mortality and blood survivin concentrations

ObjectiveSurvivin is a member of inhibitors of apoptosis proteins family. There are not data about the association between mortality of septic patients and blood survivin concentrations. Therefore, the objective of this study was to determine whether exist that association. DesignObservational and prospective study. SettingThree Spanish Intensive Care Units. PatientsPatients with sepsis or septic shock according to Sepsis-3 Consensus criteria. InterventionsSerum survivin concentrations were determined at moment of sepsis diagnosis. Main variable of interestMortality at 30 days. ResultsA total of 204 patients were included in the study, of which 75 (36.8%) died in the first 30 days. Lower age (p<0.001), serum lactic acid levels (p=0.001), rate of septic shock (p=0.001) and SOFA (p<0.001), and higher serum survivin levels (p=0.001) exhibited surviving (n=129) than non-surviving patients (n=75). We found in multiple logistic regression analysis an association between serum survivin concentrations and mortality independently of SOFA, lactic acid, age, INR, activated partial thromboplastin time (aPTT) and empiric antimicrobial treatment adequate (OR=0.968; 95% CI=0.946–0.990; p=0.005), and also independently of APACHE-II, lactic acid, platelet, INR, aPTT and empiric antimicrobial treatment adequate (OR=0.966; 95% CI=0.943–0.989; p=0.004). ConclusionsThere is an association between septic patient mortality and low blood survivin concentrations.

Immune hyporeactivity to bacteria and multiple TLR-ligands, yet no response to checkpoint inhibition in patients just after meeting Sepsis-3 criteria.

RationaleThe immune profile of sepsis patients is incompletely understood and hyperinflammation and hypoinflammation may occur concurrently or sequentially. Immune checkpoint inhibition (ICI) may counter hypoinflammation but effects are uncertain. We tested the reactivity of septic whole blood to bacteria, Toll-like receptor (TLR) ligands and to ICI.MethodsWhole blood assays of 61 patients’ samples within 24h of meeting sepsis-3 criteria and 12 age and sex-matched healthy volunteers. Measurements included pattern/danger-associated molecular pattern (P/DAMP), cytokine concentrations at baseline and in response to TLR 2, 4, and 7/8 ligands, heat-inactivated Staphylococcus aureus or Escherichia coli, E.coli lipopolysaccharide (LPS), concentration of soluble and cellular immune checkpoint molecules, and cytokine concentrations in response to ICI directed against programmed-death receptor 1 (PD1), PD1-ligand 1, or cytotoxic T-lymphocyte antigen 4, both in the absence and presence of LPS.Main resultsIn sepsis, concentrations of P/DAMPs and inflammatory cytokines were increased and the latter increased further upon incubation ex vivo. However, cytokine responses to TLR 2, 4, and 7/8 ligands, heat-inactivated S. aureus or E. coli, and E. coli LPS were all depressed. Depression of the response to LPS was associated with increased in-hospital mortality. Despite increased PD-1 expression on monocytes and T-cells, and monocyte CTLA-4 expression, however, addition of corresponding checkpoint inhibitors to assays failed to increase inflammatory cytokine concentrations in the absence and presence of LPS.ConclusionPatients first meeting Sepsis-3 criteria reveal 1) depressed responses to multiple TLR-ligands, bacteria, and bacterial LPS, despite concomitant inflammation, but 2) no response to immune checkpoint inhibition.

Ultraporous Polyquaternium-Carboxylated Chitosan Composite Hydrogel Spheres with Anticoagulant, Antibacterial, and Rapid Endotoxin Removal Profiles for Sepsis Treatment.

Hemoperfusion is an important method to remove endotoxins and save the lives of patients with sepsis. However, the current adsorbents for hemoperfusion have disadvantages of insufficient endotoxin adsorption capacity, poor blood compatibility, and so on. Herein, we proposed a novel emulsion templating (ET) method to prepare ultraporous and double-network carboxylated chitosan (CCS)-poly(diallyl dimethylammonium chloride) (PDDA) hydrogel spheres (ET-CCSPD), bearing both negative and positive charges. CCS was introduced to balance the strong positive charges of PDDA to improve hemocompatibility, and emulsion templates endowed the adsorbent with an ultraporous structure for enhanced adsorption efficacy. The ET-CCSPDs neither damaged blood cells nor activated complement responses. In addition, the activated partial thromboplastin time (APTT) was prolonged to 8.5 times, which was beneficial for reducing the injection of anticoagulant in patients. The ET-CCSPDs had excellent scavenging performance against bacteria and endotoxin, with removal ratios of 96.7% for E. coli and 99.8% for S. aureus, respectively, and the static removal ratio of endotoxin in plasma was as high as 99.1% (C0 = 5.50 EU/mL, critical illness level). An adsorption cartridge filled with the ET-CCSPDs could remove 84.7% of endotoxin within 1 h (C0 = 100 EU/mL in PBS). Interestingly, the ET-CCSPDs had a good inhibitory effect on the cytokines produced by endotoxin-mediated septic blood. By developing the ET method to prepare ultraporous and double-network adsorbents, the problems of low adsorption efficiency and poor blood compatibility of traditional endotoxin adsorbents have been solved, thus opening a new route to fabricate absorbents for blood purification.

Reply to Rezaei et al.

We read the letter of Rezaei et al. [1] with interest. We think that the most important point to bear in mind is that the lungs are very fragile organs; they suffer easily in response to the slightest aggression. This is illustrated by the fact that pulmonary complications often follow a severe acute illness, almost independently of the nature of the primary illness. One form of pulmonary aggression may well be the opening of the pleurae, as the authors mention, since this may alter respiratory mechanics. Indeed, the fact that even such seemingly slight aggression is significant is testimony to the fragility of these organs. However, the lungs may suffer in response to many other processes, some of which are well known and much more aggressive than opening the pleurae; examples include septic shock, renal/hepatic failure and blood transfusion. Many other examples may be cited, but one that particularly concerns us is the cessation of mechanical ventilation during cardiopulmonary bypass with its consequent atelectrauma and the barotrauma associated with the need for lung re-expansion prior to termination of the bypass as mentioned in our article [2]. This concerns us not only because both atelectrauma and barotrauma are well known to damage the lungs but also because they are avoidable, i.e. this is an iatrogenic complication. It is difficult to imagine that opening the pleurae could possibly even come close to such aggression. To us, it seems naive to think that the lungs would not suffer by cessation of ventilation during cardiopulmonary bypass as long as the pleural cavities are not breached.