Sepsis is a condition of life-threatening organ dysfunction caused by a dysregulated host response to infection. It is the result of a series of exaggerated physiologic responses that lead to simultaneous hyper- and hypoinflammatory states. In the hyperinflammatory phase, there is an exuberant release of cytokines, commonly referred to as a cytokine storm. The immune-suppressive phase is characterized by counterregulatory attempts to achieve homeostasis that sometimes "overshoot", leaving the host in a state of immunosuppression, thus predisposing to recurrent nosocomial and secondary infections. The aging population with comorbidities faces higher risks of immune dysfunction and inflammation. Thus, the number of sepsis survivors that develop subsequent infections is predicted to rise substantially in the next few decades. Understanding sepsis-induced immune dysregulation may enhance surveillance and outcomes. This review is intended to describe the pathophysiology of sepsis and its effects on the immune system.

Sepsis, which causes systemic inflammation and organ failure, is one of the leading causes of death in the intensive care unit (ICU) and an urgent social health problem. However, the pathogenesis and molecular mechanism of sepsis are unclear. Therefore, this study aimed to identify candidate Hub genes during sepsis progression and the candidate target genes for sepsis diagnosis and treatment.

GSE54514, GSE57065, GSE69528, GSE95233, and GSE131761 datasets were downloaded from public databases, and the differentially expressed genes (DEGs) between healthy and septic patients in each dataset were screened at adjusted P-value < 0.05 and| log2FC| ≥ 0.58. Subsequently, the obtained DEGs in each dataset were intersected to obtain the Hub genes. In addition, the DEGs between patients with better and poor prognoses in datasets GSE54514 and GSE95233 were analyzed after 28 days. The differential expression of Hub genes in septic patients with good and poor prognoses was detected at adjusted P-value < 0.05 and| log2FC| ≥ 0.58. Finally, real-time quantitative polymerase chain reaction (qRT-PCR) was used to verify the bioinformatics results.

In datasets GSE54514, GSE57065, GSE69528, GSE95233 and GSE131761, RNASE2, RNASE3, CTSG, SLPI, TNFAIP6, PGLYRP1 and BLOC1S1 were up-regulated in septic patients, and RPL10A and KLRB1 were down-regulated compared to healthy controls. qRT-PCR confirmed the expression trend of the hub genes except CTSG (which was not differentially expressed). Compared to septic patients with good prognoses, the differential expression of RNASE3 was higher in patients with poor prognoses. Furthermore, qRT-PCR revealed that KLRB1 was the only differentially expressed hub gene with down-regulated expression in sepsis patients with poor prognosis.

The candidate Hub genes closely related to sepsis include KLRB1, RNASE2, RNASE3, CTSG, SLPI, TNFAIP6, PGLYRP1, BLOC1S1, and RPL10A. KLRB1 is the most relevant candidate hub gene among these hub genes in the molecular underpinnings of sepsis, which could be targeted for sepsis detection and treatment.

We previously identified methylglyoxal as a biomarker for early identification and outcome prediction in human sepsis. We hypothesised that methylglyoxal causally impacts disease severity, and the methylglyoxal-scavenging dipeptide anserine can attenuate the detrimental effects of methylglyoxal.

Using a translational approach, secondary analyses of two observational trials were performed to test the initial hypotheses. Afterwards, these results were re-evaluated in different murine models of experimental sepsis in vivo. The detrimental effects of methylglyoxal as well as the underlying mechanisms were further assessed in vitro using transendothelial electrical resistance measurements, fluorescence-activated cell sorting analyses, cytokine assays, gene expression analyses, and enzyme activity assays, as well as immunofluorescence and immunohistochemistry staining.

The secondary analyses confirmed methylglyoxal as an independent marker associated with increased mortality within the first 48 h after sepsis onset and high catecholamine and fluid requirements in the first 24 h after sepsis onset. In the sepsis models, methylglyoxal-derived carbonyl stress significantly contributed to the development of capillary leakage by disrupting endothelial barrier-forming proteins. Mechanistically, a pathway involving the receptor of advanced glycation end products and mitogen-activated protein kinase was identified. The methylglyoxal-scavenging dipeptide anserine (β-alanyl-N-methylhistidine) reduced methylglyoxal-induced advanced glycation end-product formation and disruptions of junctional complexes in vitro. Moreover, anserine reduced capillary leakage and mortality in vivo.

Methylglyoxal causally contributes to capillary leak formation and mortality in experimental sepsis, which can be mitigated by anserine. Therefore, anserine represents an innovative therapeutic option for the treatment of septic shock.

German Research Foundation (grant number BR 4144/2-1).

This study introduces a novel Transformer-based time-series framework designed to revolutionize risk stratification in Intensive Care Units (ICUs) by predicting patient outcomes with high temporal precision. Leveraging sequential data from the eICU database, our two-stage architecture dynamically captures evolving health trajectories throughout a patient's ICU stay, enabling real-time identification of high-risk individuals and actionable insights for personalized interventions. The model demonstrated exceptional predictive power, achieving a progressive AUC increase from 0.87 (±0.021) on admission day to 0.92 (±0.009) by day 5, reflecting its capacity to assimilate longitudinal physiological patterns. Rigorous external validation across geographically diverse cohorts-including an 81.8% accuracy on Chinese sepsis data (AUC=0.73) and 76.56% accuracy on MIMIC-IV-3.1 (AUC=0.84)-confirmed robust generalizability. Crucially, SHAP-derived temporal heatmaps unveiled mortality-associated feature dynamics over time, bridging the gap between model predictions and clinically interpretable biomarkers. These findings establish a new paradigm for ICU prognostics, where data-driven temporal modeling synergizes with clinician expertise to optimize triage, reduce diagnostic latency, and ultimately improve survival outcomes in critical care.

Septic shock is associated with over 40% mortality. The immune response in septic shock is tightly regulated by cellular metabolism and transitions from early hyper-inflammation to later hypo-inflammation. Patients are susceptible to secondary infections during hypo-inflammation. The magnitude of the metabolic dysregulation and the effect of plasma metabolites on the circulating immune cells in septic shock are not reported. We hypothesized that the accumulated plasma metabolites affect the immune response in septic shock during hypo-inflammation. Our study took a unique approach. Using peripheral blood from adult septic shock patients and healthy controls, we studied: (i) Whole blood stimulation ± E. Coli lipopolysaccharide (LPS: endotoxin) to analyze plasma TNF protein, and (ii). Plasma metabolomic profile by Metabolon. Inc. (iii) We exposed peripheral blood mononuclear cells (PBMCs) from healthy controls to commercially available carbohydrate, amino acid, and fatty acid metabolites and studied the response to LPS. We report that: (i) The whole blood stimulation of the healthy control group showed a significantly upregulated TNF protein, while the septic shock group remained endotoxin tolerant, a biomarker for hypo-inflammation. (ii) A significant accumulation of carbohydrate, amino acid, fatty acid, ceramide, sphingomyelin, and TCA cycle pathway metabolites in septic shock plasma. (iii) In vitro exposure to 5 metabolites repressed while 2 metabolites upregulated the inflammatory response of PBMCs to LPS. We conclude that the endotoxin-tolerant phenotype of septic shock is associated with a simultaneous accumulation of plasma metabolites from multiple metabolic pathways, and these metabolites fundamentally influence the immune response profile of circulating cells.

Neutrophil acts as a double-edged sword in the immune system. We hypothesized that an elevated neutrophil granule protein level is associated with sepsis-associated lymphopenia (SAL).

We enrolled 61 patients with sepsis admitted to the Department of Critical Care Medicine of Peking Union Medical College Hospital between May 2022 and October 2023 in this study. Clinical and immunological parameters were recorded. Levels of neutrophil granule proteins, including myeloperoxidase (MPO) and neutrophil elastase (NE), and pyroptosis factors were examined.

Levels of neutrophil granule proteins (MPO, 82.9 vs. 175.3, p < 0 <.0001; NE, 56.3 vs. 144.2, p < 0.0001) were significantly higher in patients with sepsis with lymphopenia. Neutrophil granule protein levels were independently associated with SAL risk (MPO: OR = 1.0841, 95% CI, 1.0020-1.1730; NE: OR = 1.0540, 95% CI, 1.0040-1.1065). The area under the curve of MPO levels predicting SAL occurrence was 0.939 (95% CI, 0.846-0.984), and that of NE was 0.950 (95% CI, 0.862-0.989). Furthermore, neutrophil granule proteins were significantly correlated with CD4+ T cell and its pyroptosis [MPO and CD4+ T cells (r = -0.4039, p < 0.0001), CD4+NLRP3 (r = 0.4868, p < 0.0001), NE and CD4+ T cells (r = -0.5140, p < 0.0001), and CD4+NLRP3 (r = 0.6513, p < 0.0001)].

Increased levels of neutrophil granule proteins were significantly associated with SAL incidence, and a significant relationship between neutrophil granule proteins and the pyroptosis pathway of CD4+ T cells was revealed.

chictr.org.cn identifier ChiCTR-ROC-17010750.

Sepsis is a life-threatening organ failure resulting from a poorly regulated infection response. Organ dysfunction includes hepatic involvement, weakening the immune system due to excretory liver failure, and metabolic dysfunction, increasing the death risk. Although experimental studies correlated excretory liver functionality with immune performance and survival rates in sepsis, the proteins and pathways involved remain unclear. This study identified protein kinase C-α (PKCα) as a novel target for managing excretory liver function during sepsis. Using a preclinical murine sepsis model, we found that both PKCα knockout and the use of a PKCα-inhibitor midostaurin successfully restored liver function without hindering the host's response or ability to clear the pathogen, highlighting PKCα's vital role in excretory liver failure. In septic animals, both approaches significantly boosted survival rates. Midostaurin is the clinically approved active pharmaceutical ingredient in Rydapt, approved for the adjuvant treatment of FTL3-mutated AML. Here, it reduced plasma bile acids and related inflammation in those patients, opening a translational avenue for therapeutics in sepsis. Conclusively, our research underscores the significance of PKCα in controlling excretory liver function during inflammation. This suggests that targeting this protein could restore liver function without compromising the immune system, thereby decreasing sepsis mortality and supporting the recent paradigm that the liver is a hub for the host response to infection that might, in the future, result in novel host-directed therapies supporting the current state-of-the-art intensive care medicine in patients with sepsis-associated liver failure.

Sepsis is a life-threatening syndrome characterized by organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated acute liver injury (SA-ALI) is a frequent and serious complication of sepsis that considerably impacts both short-term and long-term survival outcomes. In intensive care units (ICUs), the mortality rate of patients with SA-ALI remains high, mostly due to the absence of effective early diagnostic markers and suitable therapeutic strategies. Recent studies have demonstrated the importance of non-coding RNAs (ncRNAs) in the development and progression of SA-ALI. This review focuses on the critical roles of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in regulating "cytokine storms", oxidative stress, mitochondrial dysfunction, and programmed cell death in SA-ALI, and summarizes the current state and limitations of existing studies on lncRNAs and circRNAs in SA-ALI. By integrating advancements in high-throughput sequencing technologies, this review provides novel insights into the dual potential of ncRNAs as diagnostic biomarkers and therapeutic targets, offers new ideas for SA-ALI diagnosis and treatment research and highlights potential challenges in clinical translation.

Interleukin-6 (IL-6) plays a central role in sepsis-induced cytokine storm involving immune hyperactivation and early neutrophil activation. Programmed death protein-1 (PD-1) is associated with sepsis-induced immunosuppression and lymphocyte apoptosis. However, the effects of simultaneous blockade of IL-6 and PD-1 in a murine sepsis model are not well understood.

In this study, sepsis was induced in male C57BL/6 mice through cecal ligation and puncture (CLP). IL-6 blockade, PD-1 blockade, or combination of both was administered 24 h after CLP. Peripheral blood count, cytokine level, lymphocyte apoptosis in the spleen, neutrophil infiltration in the lungs and liver, and survival rate were measured. The mortality rate of the IL-6/PD-1 group was lower, though not statistically significant (p = 0.164), than that of CLP mice (75.0% vs. 91.7%). The IL-6/PD-1 group had lower neutrophil percentage and platelet count compared with the CLP group; no significant difference was observed in other cytokine levels. The IL-6/PD-1 group also showed reduced T lymphocyte apoptosis in the spleen and decreased neutrophil infiltration in the liver and lungs.

IL-6/PD-1 dual blockade reduces neutrophil infiltration, lymphocyte apoptosis, and bacterial burden while preserving tissue integrity in sepsis. Although the improvement in survival was not statistically significant, these findings highlight its potential as a therapeutic approach in sepsis.

Critical illness-associated immune dysfunction (CIID) is prevalent in the ICU and frequently resulted in uncontrollably immune responses. Critical immunological dysfunction is understood to be important, although there are currently no clinically accepted diagnostic criteria for it. Given this, we examined the literature and developed an initial diagnostic criterion that we validated using the MIMIC-IV database.

We searched the related literature in the last 32 years. Patients admitted to the ICU for the first time were selected by screening the MIMIC-IV database. Different criteria were used to categorize patients into groups related to immune dysfunction (ID) and non-immune dysfunction (NID). Within the ID group, patients were subdivided into three subgroups: hyperinflammatory (HI), immunosuppression (IS), and a subgroup combining immunosuppression and hyperinflammation (HI+IS). The APACHE II was used to measure the patients' severity. The association between immune dysfunction and mortality after 30 or 180 days was evaluated through the KM curves and COX regression analysis.

By summarizing relevant literature, we proposed the initial diagnostic criteria. The analysis included 43,965 patients, with approximately 77% meeting the diagnostic criteria for CIID. We observed that patients with immune dysfunction possessed higher APACHE II scores and there were differences in peak APACHE II among the three subgroups. When comparing patients' 30-day mortality in the COX model, it is evident that patients in the IS subgroup had the lowest risk and patients in the HI subgroup the greatest risk after accounting for all covariates. In contrast, patients in the IS subgroup had the highest risk of death, those in the HI subgroup had the lowest risk when comparing long-term mortality. In summary, we propose and validate diagnostic criteria related to CIID. Subgroup analyses were carried out, which also revealed variations between the three groups.

The diagnostic criteria were confirmed by the MIMIC-IV database, demonstrating the diagnostic criteria were scientifically valid and reliable.

Sepsis is characterized by a concomitant early pro-inflammatory response by immune cells to an infection, and an opposing anti-inflammatory response that results in protracted immunosuppression. The primary pathological event in sepsis is widespread programmed cell death, or cellular self-sacrifice, of innate and adaptive immune cells, leading to profound immunological suppression. This severe immune dysfunction hampers effective primary pathogen clearance, thereby increasing the risk of secondary opportunistic infections, latent viral reactivation, multiple organ dysfunction, and elevated mortality. The types of cell death include apoptosis (type I programmed cell death), autophagy (type II programmed cell death), NETosis (a program for formation of neutrophil extracellular traps (NETs)) and other programmed cell deaths like pyroptosis, ferroptosis, necroptosis, each contributing to immunosuppression in distinct ways during the later phases of sepsis. Extensive apoptosis of lymphocytes, such as CD4+, CD8+ T cells, and B cells, is strongly associated with immunosuppression. Apoptosis of dendritic cells further compromises T and B cell survival and can induce T cell anergy or promote regulatory Treg cell proliferation. Moreover, delayed apoptosis and impaired neutrophil function contribute to nosocomial infections and immune dysfunction in sepsis. Interestingly, aberrant NETosis and the subsequent depletion of mature neutrophils also trigger immunosuppression, and neutrophil pyroptosis can positively regulate NETosis. The interaction between programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1) plays a key role in T cell modulation and neutrophil apoptosis in sepsis. The dendritic cell growth factor, Fms-like tyrosine kinase (FLTEL), increases DC numbers, enhances CD 28 expression, attenuates PD-L1, and improves survival in sepsis. Recently, immunoadjuvant therapies have attracted attention for their potential to restore host physiological immunity and homeostasis in patients with sepsis. This review focuses on several potential immunotherapeutic agents designed to bolster suppressed innate and adaptive immune responses in the management of sepsis.

Despite continued improvement in post-sepsis survival, long term morbidity and mortality remain high. Chronic critical illness (CCI), defined as persistent inflammation and organ injury requiring prolonged intensive care, is a harbinger of poor long-term outcomes in sepsis survivors. Current dogma states that sepsis survivors are immunosuppressed, particularly in CCI. Investigation of this immune suppression in heterogeneous immune populations across distinct clinical trajectories and outcomes, along with limited sampling access, is accessible via single-cell RNA sequencing (scRNA-seq).

scRNA-seq analysis was performed on healthy subjects (n=12), acutely septic patients at day 4 ± 1 (n=4), and those defined as rapid recovery (n=4) or CCI (n=5) at day 14-21. Differential gene expression and pathway analyses were performed on peripheral blood lymphocytes at both a population and annotated cell subset level. Cellular function was assessed via enzyme-linked immunosorbent spot (ELISpot), cytokine production analysis, and T-cell proliferation assays on an additional cohort of septic patients (19 healthy, 68 acutely septic, 27 rapid recovery and 20 classified as CCI 14-21 days after sepsis onset).

Sepsis survivors that developed CCI exhibited proportional shifts within lymphoid cell populations, with expanded frequency of CD8+ and NK cells. Differential expression and pathway analyses revealed continued activation in T cells and NK cells, with generalized suppression of B-cell function. Both T and NK cell subsets displayed transcriptomic profiles of exhaustion and immunosuppression in CCI, particularly in CD8+ T effector memory (TEM) cells and NK cells. Functional validation of T-cell behavior in an independent cohort demonstrated T cells maintained proliferative responses in vitro yet exhibited a marked loss of cytokine production. IFN-γ production at the acute phase (day 4 ± 1) was significantly reduced in subjects later classified as CCI.

Sepsis patients exhibit unique T-, B-, and NK-cell transcriptional patterns that are both time- and clinical trajectory-dependent. These transcriptomic and pathway differences in sepsis patients that develop CCI are associated with exhaustion in CD8+ TEM cells and NK cells. Understanding the specific immune system patterns of different cell subsets after sepsis at a molecular level will be key to the development of personalized immunotherapy and drug-targeting intervention.

https://clinicaltrials.gov/, identifier NCT02276417.

Ubiquitin regulatory X (UBX) domain-containing protein 6 (UBXN6) is an essential cofactor for the activity of the valosin-containing protein p97, an adenosine triphosphatase associated with diverse cellular activities. Nonetheless, its role in cells of the innate immune system remains largely unexplored. In this study, we report that UBXN6 is upregulated in humans with sepsis and may serve as a pivotal regulator of inflammatory responses via the activation of autophagy. Notably, the upregulation of UBXN6 in sepsis patients was negatively correlated with inflammatory gene profiles but positively correlated with the expression of Forkhead box O3, an autophagy-driving transcription factor. Compared with those of control mice, the macrophages of mice subjected to myeloid cell-specific UBXN6 depletion exhibited exacerbated inflammation, increased mitochondrial oxidative stress, and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways. UBXN6-deficient macrophages also exhibited immunometabolic remodeling, characterized by a shift to aerobic glycolysis and elevated levels of branched-chain amino acids. These metabolic shifts amplify mammalian target of rapamycin pathway signaling, in turn reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis. Together, these data reveal that UBXN6 serves as an activator of autophagy and regulates inflammation to maintain immune system suppression during human sepsis.

Autophagy serves as a critical regulator of immune responses in sepsis. Macrophages are vital constituents of both innate and adaptive immunity. In this study, we delved into the intricate role of p120-catenin (p120) in orchestrating autophagy in macrophages in response to endotoxin stimulation. Depletion of p120 effectively suppressed LPS-induced autophagy in both J774A.1 macrophages and murine bone marrow-derived macrophages. LPS not only elevated the interaction between p120 and L chain 3 (LC3) I/II but also facilitated the association of p120 with mammalian target of rapamycin (mTOR). p120 depletion in macrophages by small interfering RNA reduced LPS-induced dissociation of mTOR and Unc-51-like kinase 1 (ULK1), leading to an increase in the phosphorylation of ULK1. p120 depletion also enhanced LPS-triggered macrophage apoptosis, as evidenced by increased levels of cleaved caspase 3, 7-aminoactinomycin D staining, and TUNEL assay. Notably, inhibiting autophagy reversed the decrease in apoptosis caused by LPS stimulation in macrophages overexpressing p120. Additionally, the ablation of p120 inhibited autophagy and accentuated apoptosis in alveolar macrophages in LPS-challenged mice. Collectively, our findings strongly suggest that p120 plays a pivotal role in fostering autophagy while concurrently hindering apoptosis in macrophages, achieved through modulation of the mTOR/ULK1 signaling pathway in sepsis. This underscores the potential of targeting macrophage p120 as an innovative therapeutic avenue for treating inflammatory disorders.

In a previous study, we described elevated anti-Anisakis IgG levels in septic patients in relation to disease severity. In this study, our objective was to analyze the evolution of anti-Anisakis immunoglobulins in septic patients during hospital admission and their association with αβ and γδ T cell subsets.

We recruited 80 subjects: 40 patients with sepsis and 40 controls. αβ and γδ T cells were analyzed using flow cytometry. Apoptosis was also assessed, and anti-Anisakis antibodies were measured by ELISA in the sera of patients with sepsis and controls.

In the second analysis (7-10 after sepsis evolution), an increase in all specific antibody isotypes was identified in individuals with septic shock, except IgE. The levels of anti-Anisakis IgG and IgA were higher in the subjects with sepsis in the first analysis and continued to increase in the second analysis compared with the healthy control subjects. There was an increase in anti-Anisakis IgG and IgA levels in surviving patients and an increase in IgA levels in non-surviving patients. A rise in specific IgG and IgE levels was noted in the second analysis of patients with sepsis with αβ CD3+ T cell deficiency. Patients without γδ T cell deficiency had increased anti-Anisakis IgA levels 7-10 days after admission.

Our results suggest a previous infection by Anisakis that could be involved in the subsequent septic process and be related to patients who have negative cultures in which the pathogen causing sepsis has not been identified.

Sepsis causes substantial morbidity and mortality and constitutes a major public health problem. In patients with sepsis, immunosuppression is associated with poor prognosis, and immune monitoring during the early stages has prognostic value. This study aims to explore immunologic parameters associated with sepsis prognosis, potentially identifying patients who may benefit from immunotherapy, improving intensive care survival.

A total of 65 patients with sepsis from the Department of Emergency Medicine were divided based on survival at 28 days (47 in the survival group, 18 in the non-survival group). Peripheral blood was collected to measure absolute lymphocyte count and T lymphocyte subpopulations, including the percentage and absolute count of total T cells, CD4+ T, CD8+ T, and NK cells, and the percentages of naïve CD4+ T, central memory CD4+ T, effector CD4+ T, effector memory CD4+ T, naïve CD8+ T, central memory CD8+ T, effector CD8+ T, effector memory CD8+ T, CD4+HLA-DR+ T, and CD8+HLA-DR+ T cells, and Tregs. The differences in these parameters between the two groups were compared and a regression model was constructed to identify possible risk factors for death in patients with sepsis.

The absolute lymphocyte count, absolute T cell count (CD3+, CD4+, and CD8+) and naïve CD4+ T cell percentage were significantly lower in the non-survival group. Conversely, Tregs were higher in patients who did not survive sepsis. In regression analysis, the absolute lymphocyte count and naïve CD4+ T cell percentage remained statistically significant. The receiver operating characteristic curve showed that a model based on the absolute lymphocyte count (435 cells/µL) and naïve CD4+ T cell percentage (20.25%) performed best in predicting sepsis prognosis.

Monitoring of absolute lymphocyte count and analysis of T cell subtypes in the early phase of sepsis is predictive of outcome and may help identify those patients who would benefit from immunotherapy, improving survival.

To explore the relationship between hypernatremia and 28-day mortality in elderly sepsis patients.

A total of 179 elderly patients (age ≥65 years) with elevated serum sodium admitted to the Department of Critical Care Medicine of Nanjing Hospital affiliated with Nanjing Medical University from September 2021 to September 2022 were included in this retrospective observational study. The clinical data of all patients were collected, and the patients were divided into septic group and nonseptic groups according to the Sepsis 3.0 definition. The clinical features, acute physiological and chronic health II score (APACHE II score), mechanical ventilation time, serum sodium value and duration of serum sodium elevation were compared between the two groups. ROC curves were drawn to evaluate the predictive value of each index on the prognosis of sepsis patients, and Kaplan‒Meier survival analysis was carried out on patients with different serum sodium peaks.

(1) The changes in serum sodium within 48 hours after admission in the sepsis group were small and statistically significant compared with those in the nonsepsis group (P = 0.039); however, the serum sodium elevation duration was longer (P = 0.018). (2) Compared with nonseptic patients, the 7-day mortality of septic patients was higher (15.8 vs. 7.7, P<0.001). The 28-day mortality of septic patients was higher than that of nonseptic patients, but there was no significant difference between the two groups (P = 0.086). (3) The serum sodium level in the sepsis group was higher than that in the nonsepsis group on the 1st, 3rd, 5th and 7th days (P<0.001). There was no significant difference in mechanical ventilation time or duration of stay in the ICU between the two groups. (4) The ROC curve analysis showed that the peak value of serum sodium had predictive value for the prognosis severity of elderly patients with sepsis. The area under the curve (AUC) was 0.753, the 95% confidence interval (95% CI) was 0.639~0.867, and the best cut-off value was 154.9 mmol/L. (5) According to the best cut-off value of the serum sodium peak, the septic patients were divided into two groups: the peak value of serum sodium was ≥154.9 mmol/L (group A), and the peak value of serum sodium was <154.9 mmol/L (group B). Among them, the case fatality rate was higher at 7 days and 28 days when the peak value of serum sodium was ≥154.9 mmol/L (group A) (22.0% vs. 8.6%); the χ2 value was 35.379, P<0.05; 75.6% vs. 37.1%, χ2 = 14.21, P = 0.003). There was no significant difference in mechanical ventilation time or duration of stay in the ICU between the two groups. (6) Kaplan‒Meier survival analysis showed that the median survival time of patients with a serum sodium peak ≥154.9 mmol/L (group A) was significantly shorter than that of patients with a serum sodium peak < 154.9 mmol/L (group B) (16.7±1.4 d vs. 24.8±1.2 d, P <0.05).

The serum sodium increase in elderly sepsis patients lasts for a long time, and the serum sodium fluctuation is relatively small. The serum sodium peak value has predictive value for 28-day mortality.

Sepsis remains a major global public health challenge. The host's response in sepsis involves both an exaggerated inflammatory reaction and immunosuppressive mechanisms. A better understanding of this response has shed light on the failure of anti-inflammatory therapies administered under the 'one size fits all' approach during the last decades.

To date, patients' management has moved toward a comprehensive precision medicine approach that aims to personalize immunotherapy, whether anti-inflammatory or immunostimulatory. Large Prospective interventional randomized controlled trials validating this approach are about to start. A crucial prerequisite for these studies is to stratify patients based on biomarkers that will help defining the patients' immuno-inflammatory trajectory.

Some biomarkers are already available in routine clinical care, while improvements are anticipated through the standardized use of transcriptomics and other multi-omics technologies in this field. With these precautions in mind, it is reasonable to anticipate improvement in outcomes in sepsis.

Sepsis presents a challenge due to its complex immune responses, where balance between inflammation and anti-inflammation is critical for survival. Glucocorticoid-induced leucine zipper (GILZ) is key protein in achieving this balance, suppressing inflammation and mediating glucocorticoid response. This study aims to investigate GILZ transcript variants in sepsis patients and explore their potential for patient stratification and optimizing glucocorticoid therapy.

Sepsis patients meeting the criteria outlined in Sepsis-3 were enrolled, and RNA was isolated from whole blood samples. Quantitative mRNA expression of GILZ transcript variants in both sepsis patient samples (n = 121) and the monocytic U937 cell line (n = 3), treated with hydrocortisone and lipopolysaccharides, was assessed using quantitative PCR (qPCR).

Elevated expression of GILZ transcript variant 1 (GILZ TV 1) serves as a marker for heightened 30-day mortality in septic patients. Increased levels of GILZ TV 1 within the initial day of sepsis onset are associated with a 2.2-[95% CI 1.2-4.3] fold rise in mortality, escalating to an 8.5-[95% CI 2.0-36.4] fold increase by day eight. GILZ TV1 expression is enhanced by glucocorticoids in cell culture but remains unaffected by inflammatory stimuli such as LPS. In septic patients, GILZ TV 1 expression increases over the course of sepsis and in response to hydrocortisone treatment. Furthermore, a high expression ratio of transcript variant 1 relative to all GILZ mRNA TVs correlates with a 2.3-fold higher mortality rate in patients receiving hydrocortisone treatment.

High expression of GILZ TV 1 is associated with a higher 30-day sepsis mortality rate. Moreover, a high expression ratio of GILZ TV 1 relative to all GILZ transcript variants is a parameter for identifying patient subgroups in which hydrocortisone may be contraindicated.

Sepsis has been a major health problem for centuries and it is still the leading cause of hospital deaths. Several studies in the past decades have identified numerous biochemical abnormalities in severe cases, and many of these studies provide evidence of the perturbation of the hemostatic system. This can result in complications, such as disseminated intravascular coagulation that can lead to multiorgan failure. Nevertheless, large clinical studies have demonstrated that the simple approach of inhibiting the coagulation processes by any means fails to provide significant improvement in the survival of septic patients. A cause of this failure could be the fact that in sepsis the major clinical problems result not primarily from the presence of the infective agent or enhanced coagulation but from the complex dysregulated systemic host response to pathogens. If this overt reaction is not fully deciphered, appropriate interference is highly unlikely and any improvement by conventional therapeutic interventions would be limited. Cellular activation in sepsis can be targeted by novel approaches like inhibition of the heterotypic cellular interactions of blood cells by targeting surface receptors or posttranscriptional control of the hemostatic system by noncoding ribonucleic acid (RNA) molecules. Stable RNA molecules can affect the expression of several proteins. Thus, it can be anticipated that modulation of microRNA production would result in a multitude of effects that may be beneficial in septic cases. Here, we highlight some of the recent diagnostic possibilities and potential novel routes of the dysregulated host response.

Immune cell dysfunction plays a central role in sepsis-induced immunoparalysis. Targeted treatment using healthy donor immune cell transfusions, particularly granulocyte concentrates (GC) potentially induces tissue damage. Initial trials using GC in an extracorporeal immune cell perfusion system provided evidence for beneficial effects with fewer side effects, by separating patient and donor immune cell compartments. A multicenter clinical trial is exploring feasibility and effects of a 6-h treatment (NCT06143137). This ex vivo study examines technical feasibility and cellular effects of an extended treatment interval up to 24 h.

Standard GC were purified to increase the potential storage time and subsequently implemented in the extracorporeal immune cell perfusion system. Parameters assessed included cell viability, phagocytosis activity, oxidative burst, cytokine release, and metabolic parameters of purified. GC during an extended circulation time of up to 24 h.

After storage of 72 h granulocytes were viable throughout the study period and exhibited preserved functionality and metabolic activity. The findings highlight a time-dependent nature of cytokine release by neutrophils in the extracorporeal circuit, as cytokine secretion patterns showed IL-8 peaking within 6 h, while MCP-1, IL-6, IL-1β, and TNF-α increased after 24 h of circulation.

Purified GC remain functional after 72 h of storage and additional 24 h in the circulating treatment model. Cytokine secretion patterns revealed a significant increase, especially between 10 and 24 h of treatment. Extending treatment time holds promise for enhancing immune response against sepsis-induced immunoparalysis. These findings provide valuable insights for optimizing immune-targeted therapeutic interventions.

Sepsis is among the most important causes of mortality, particularly within the elderly population. Sepsis prevalence is on the rise due to different factors, including increasing average population age and the concomitant rise in the prevalence of frailty and chronic morbidities. Recent investigations have unveiled a "trimodal" trajectory for sepsis-related mortality, with the ultimate zenith occurring from 60 to 90 days until several years after the original insult. This prolonged temporal course ostensibly emanates from the sustained perturbation of immune responses, persevering beyond the phase of clinical convalescence. This phenomenon is particularly associated with the aging immune system, characterized by a broad dysregulation commonly known as "inflammaging." Inflammaging associates with a chronic low-grade activation of the innate immune system preventing an appropriate response to infective agents. Notably, during the initial phases of sepsis, neutrophils-essential in combating pathogens-may exhibit compromised activity. Paradoxically, an overly zealous neutrophilic reaction has been observed to underlie multi-organ dysfunction during the later stages of sepsis. Given this scenario, discovering treatments that can enhance neutrophil activity during the early phases of sepsis while curbing their overactivity in the later phases could prove beneficial in fighting pathogens and reducing the detrimental effects caused by an overactive immune system. This narrative review delves into the potential key role of neutrophils in the pathological process of sepsis, focusing on how the aging process impacts their functions, and highlighting possible targets for developing immune-modulatory therapies. Additionally, the review includes tables that outline the principal potential targets for immunomodulating agents.

Alcohol use disorder, reported by 1 in 8 critically ill patients, is a risk factor for death in sepsis patients. Sepsis, the leading cause of death, kills over 270,000 patients in the United States alone and remains without targeted therapy. Immune response in sepsis transitions from an early hyperinflammation to persistent inflammation and immunosuppression and multiple organ dysfunction during late sepsis. Innate immunity is the first line of defense against pathogen invasion. Ethanol exposure is known to impair innate and adaptive immune response and bacterial clearance in sepsis patients. Specifically, ethanol exposure is known to modulate every aspect of innate immune response with and without sepsis. Multiple molecular mechanisms are implicated in causing dysregulated immune response in ethanol exposure with sepsis, but targeted treatments have remained elusive. In this article, we outline the effects of ethanol exposure on various innate immune cell types in general and during sepsis.

Sepsis results from systemic, dysregulated inflammatory responses to infection, culminating in multiple organ failure. Here, we demonstrate the utility of CD5L for treating experimental sepsis caused by cecal ligation and puncture (CLP). We show that CD5L's important features include its ability to enhance neutrophil recruitment and activation by increasing circulating levels of CXCL1, and to promote neutrophil phagocytosis. CD5L-deficient mice exhibit impaired neutrophil recruitment and compromised bacterial control, rendering them susceptible to attenuated CLP. CD5L-/- peritoneal cells from mice subjected to medium-grade CLP exhibit a heightened pro-inflammatory transcriptional profile, reflecting a loss of control of the immune response to the infection. Intravenous administration of recombinant CD5L (rCD5L) in immunocompetent C57BL/6 wild-type (WT) mice significantly ameliorates measures of disease in the setting of high-grade CLP-induced sepsis. Furthermore, rCD5L lowers endotoxin and damage-associated molecular pattern (DAMP) levels, and protects WT mice from LPS-induced endotoxic shock. These findings warrant the investigation of rCD5L as a possible treatment for sepsis in humans.

In the last decades, several adjunctive treatments have been proposed to reduce mortality in septic shock patients. Unfortunately, mortality due to sepsis and septic shock remains elevated and NO trials evaluating adjunctive therapies were able to demonstrate any clear benefit. In light of the lack of evidence and conflicting results from previous studies, in this multidisciplinary consensus, the authors considered the rational, recent investigations and potential clinical benefits of targeted adjunctive therapies.

A panel of multidisciplinary experts defined clinical phenotypes, treatments and outcomes of greater interest in the field of adjunctive therapies for sepsis and septic shock. After an extensive systematic literature review, the appropriateness of each treatment for each clinical phenotype was determined using the modified RAND/UCLA appropriateness method.

The consensus identified two distinct clinical phenotypes: patients with overwhelming shock and patients with immune paralysis. Six different adjunctive treatments were considered the most frequently used and promising: (i) corticosteroids, (ii) blood purification, (iii) immunoglobulins, (iv) granulocyte/monocyte colony-stimulating factor and (v) specific immune therapy (i.e. interferon-gamma, IL7 and AntiPD1). Agreement was achieved in 70% of the 25 clinical questions.

Although clinical evidence is lacking, adjunctive therapies are often employed in the treatment of sepsis. To address this gap in knowledge, a panel of national experts has provided a structured consensus on the appropriate use of these treatments in clinical practice.

Background: The mechanisms underlying the increased mortality of secondary infections during the immunosuppressive phase of sepsis remain elusive. Objectives: We sought to investigate the role of Siglec-F+ neutrophils on splenic T lymphocytes in the immunosuppressed phase of sepsis and on secondary infection in PICS mice, and to elucidate the underlying mechanisms. Methods: We established a mouse model of sepsis-induced immunosuppression followed by secondary infection with LPS or E. coli. The main manifestation of immunosuppression is the functional exhaustion of splenic T lymphocytes. Treg depletion reagent Anti-IL-2, IL-10 blocker Anti-IL-10R, macrophage depletion reagent Liposomes, neutrophil depletion reagent Anti-Ly6G, neutrophil migration inhibitor SB225002, Siglec-F depletion reagent Anti-Siglec-F are all used on PICS mice. The function of neutrophil subsets was investigated by adoptive transplantation and the experiments in vitro. Results: Compared to other organs, we observed a significant reduction in pro-inflammatory cytokines in the spleen, accompanied by a marked increase in IL-10 production, primarily by infiltrating neutrophils. These infiltrating neutrophils in the spleen during the immunosuppressive phase of sepsis undergo phenotypic change in the local microenvironment, exhibiting high expression of neutrophil biomarkers such as Siglec-F, Ly6G, and Siglec-E. Depletion of neutrophils or specifically targeting Siglec-F leads to enhance the function of T lymphocytes and a notable improvement in the survival of mice with secondary infections. Conclusions: We identified Siglec-F+ neutrophils as the primary producers of IL-10, which significantly contributed to T lymphocyte suppression represents a novel finding with potential therapeutic implications.

Globally, sepsis and pneumonia account for significant mortality and morbidity. A complex interplay of immune-molecular pathways underlies both sepsis and pneumonia, resulting in similar and overlapping disease characteristics. Sepsis could result from unmanaged pneumonia. Similarly, sepsis patients have pneumonia as a common complication in the intensive care unit. A significant percentage of pneumonia is misdiagnosed as septic shock. Therefore, our knowledge of the clinical relationship between pneumonia and sepsis is imperative to the proper management of these syndromes. Regarding pathogenesis and etiology, pneumococcus is one of the leading pathogens implicated in both pneumonia and sepsis syndromes. Growing evidence suggests that pneumococcal pneumonia can potentially disseminate and consequently induce systemic inflammation and severe sepsis. Streptococcus pneumoniae could potentially exploit the function of dendritic cells (DCs) to facilitate bacterial dissemination. This highlights the importance of pathogen-immune cell crosstalk in the pathophysiology of sepsis and pneumonia. The role of DCs in pneumococcal infections and sepsis is not well understood. Therefore, studying the immunologic crosstalk between pneumococcus and host immune mediators is crucial to elucidating the pathophysiology of pneumonia-induced lung injury and sepsis. This knowledge would help mitigate clinical diagnosis and management challenges.

Sepsis is characterised by a dysregulated host immune response to infection. Despite recognition of its significance, immune status monitoring is not implemented in clinical practice due in part to the current absence of direct therapeutic implications. Technological advances in immunological profiling could enhance our understanding of immune dysregulation and facilitate integration into clinical practice. In this Review, we provide an overview of the current state of immune profiling in sepsis, including its use, current challenges, and opportunities for progress. We highlight the important role of immunological biomarkers in facilitating predictive enrichment in current and future treatment scenarios. We propose that multiple immune and non-immune-related parameters, including clinical and microbiological data, be integrated into diagnostic and predictive combitypes, with the aid of machine learning and artificial intelligence techniques. These combitypes could form the basis of workable algorithms to guide clinical decisions that make precision medicine in sepsis a reality and improve patient outcomes.

Sepsis-surviving adult individuals commonly develop immunosuppression and increased susceptibility to secondary infections, an outcome mediated by the axis IL-33/ILC2s/M2 macrophages/Tregs. Nonetheless, the long-term immune consequences of paediatric sepsis are indeterminate. We sought to investigate the role of age in the genesis of immunosuppression following sepsis.

Here, we compared the frequency of Tregs, the activation of the IL-33/ILC2s axis in M2 macrophages and the DNA methylation of epithelial lung cells from post-septic infant and adult mice. Likewise, sepsis-surviving mice were inoculated intranasally with Pseudomonas aeruginosa or by subcutaneous inoculation of the B16 melanoma cell line. Finally, blood samples from sepsis-surviving patients were collected and the concentration of IL-33 and Tregs frequency were assessed.

In contrast to 6-week-old mice, 2-week-old mice were resistant to secondary infection and did not show impairment in tumour controls upon melanoma challenge. Mechanistically, increased IL-33 levels, Tregs expansion, and activation of ILC2s and M2-macrophages were observed in 6-week-old but not 2-week-old post-septic mice. Moreover, impaired IL-33 production in 2-week-old post-septic mice was associated with increased DNA methylation in lung epithelial cells. Notably, IL-33 treatment boosted the expansion of Tregs and induced immunosuppression in 2-week-old mice. Clinically, adults but not paediatric post-septic patients exhibited higher counts of Tregs and seral IL-33 levels.

These findings demonstrate a crucial and age-dependent role for IL-33 in post-sepsis immunosuppression. Thus, a better understanding of this process may lead to differential treatments for adult and paediatric sepsis.

Treatment failure and clinical stability are important outcomes in community-acquired pneumonia (CAP). It is essential to know the causes and risk factors for treatment failure and delay in reaching clinical stability in CAP. The study of both as well as the associated underlying mechanisms and host response are key to improving outcomes in pneumonia.

Sepsis is one of the most serious hospital conditions associated with high mortality. Sepsis is the result of a dysregulated immune response to infection that can lead to multiple organ dysfunction and death. Due to the wide variability in the causes of sepsis, clinical presentation, and the recovery trajectories, identifying sepsis sub-phenotypes is crucial to advance our understanding of sepsis characterization, to choose targeted treatments and optimal timing of interventions, and to improve prognostication. Prior studies have described different sub-phenotypes of sepsis using organ-specific characteristics. These studies applied clustering algorithms to electronic health records (EHRs) to identify disease sub-phenotypes. However, prior approaches did not capture temporal information and made uncertain assumptions about the relationships among the sub-phenotypes for clustering procedures.

We developed a time-aware soft clustering algorithm guided by clinical variables to identify sepsis sub-phenotypes using data available in the EHR.

We identified six novel sepsis hybrid sub-phenotypes and evaluated them for medical plausibility. In addition, we built an early-warning sepsis prediction model using logistic regression.

Our results suggest that these novel sepsis hybrid sub-phenotypes are promising to provide more accurate information on sepsis-related organ dysfunction and sepsis recovery trajectories which can be important to inform management decisions and sepsis prognosis.

The global burden of invasive fungal infections (IFIs) is emerging in immunologic deficiency status from various disease. Patients with acute-on-chronic hepatitis B liver failure (ACHBLF) are prone to IFI and their conditions are commonly exacerbated by IFI. However, little is known about the characteristics and risk factors for IFI in hospitalized ACHBLF patients.

A total of 243 hospitalized ACHBLF patients were retrospectively enrolled from January 2010 to July 2023. We performed restricted cubic spline analysis to determine the non-linear associations between independent variables and IFI. The risk factors for IFI were identified using logistic regression and the extreme gradient boosting (XGBoost) algorithm. The effect values of the risk factors were determined by the SHapley Additive exPlanations (SHAP) method.

There were 24 ACHBLF patients (9.84%) who developed IFI on average 17.5 (13.50, 23.00) days after admission. The serum creatinine level showed a non-linear association with the possibility of IFI. Multiple logistic regression revealed that length of hospitalization (OR = 1.05, 95% CI: 1.02-1.08, P = 0.002) and neutrophilic granulocyte percentage (OR = 1.04, 95% CI: 1.00-1.09, P = 0.042) were independent risk factors for IFI. The XGBoost algorithm showed that the use of antibiotics (SHAP value = 0.446), length of hospitalization (SHAP value = 0.406) and log (qHBV DNA) (SHAP value = 0.206) were the top three independent risk factors for IFI. Furthermore, interaction analysis revealed no multiplicative effects between the use of antibiotics and the use of glucocorticoids (P = 0.990).

IFI is a rare complication that leads to high mortality in hospitalized ACHBLF patients, and a high neutrophilic granulocyte percentage and length of hospitalization are independent risk factors for the occurrence of IFI.

Sepsis is a potentially fatal condition characterized by organ dysfunction caused by an imbalanced immune response to infection. Although an increased inflammatory response significantly contributes to the pathogenesis of sepsis, several molecular mechanisms underlying the progression of sepsis are associated with increased cellular reactive oxygen species (ROS) generation and exhausted antioxidant pathways. This review article provides a comprehensive overview of the involvement of ROS in the pathophysiology of sepsis and the potential application of antioxidants with antimicrobial properties as an adjunct to primary therapies (fluid and antibiotic therapies) against sepsis. This article delves into the advantages and disadvantages associated with the utilization of antioxidants in the therapeutic approach to sepsis, which has been explored in a variety of animal models and clinical trials. While the application of antioxidants has been suggested as a potential therapy to suppress the immune response in cases where an intensified inflammatory reaction occurs, the use of multiple antioxidant agents can be beneficial as they can act additively or synergistically on different pathways, thereby enhancing the antioxidant defense. Furthermore, the utilization of immunoadjuvant therapy, specifically in septic patients displaying immunosuppressive tendencies, represents a promising advancement in sepsis therapy.

As sepsis progresses, immune cell apoptosis plays regulatory roles in the pathogenesis of immunosuppression and organ failure. We previously reported that adenosine deaminases acting on RNA-1 (ADAR1) reduced intestinal and splenic inflammatory damage during sepsis. However, the roles and mechanism of ADAR1 in sepsis-induced liver injury remain unclear.