Background : Sepsis is characterized by a dysregulated host response. Patients with prior solid organ transplantation (SOT) are highly susceptible to infection due to chronic immunosuppression, yet exhibit improved survival once sepsis occurs. The underlying mechanisms remain poorly understood. Methods : We analyzed a prospective multicenter cohort of septic intensive care unit patients (SepsisDataNet.NRW; n=538). Clinical outcomes were assessed using Kaplan-Meier analysis and multivariable Cox regression. Immune profiling included serum cytokines, flow cytometric immunophenotyping, plasma proteomics, and intracellular signaling using proximity ligation assays (PLA) in peripheral blood mononuclear cells (PBMCs). To reduce clinical confounding, ex vivo lipopolysaccharide (LPS) stimulation experiments were performed in PBMCs of a non-septic kidney transplantation cohort (e:kid; n=10) obtained before and after organ-transplantation. Results : SOT patients demonstrated improved 30-day survival compared with non-SOT patients (84% vs. 66%; adjusted HR 0.49, 95% CI 0.26-0.95). Cytokine analysis revealed reduced IL-6 and TNF-α levels, alongside increased IL-18, indicating attenuation of hyperinflammation with preserved innate activation. Flow cytometry showed reductions in adaptive immune cells but relatively preserved innate immune function, reflected by higher monocytic HLA-DR expression. Proteomics identified enrichment of innate immune, complement, lipid metabolic response networks. At cellular level, SOT patients exhibited increased GLUT1 expression and enhanced TFAM/TFB2M interaction, indicating coordinated immunometabolism. Conclusion : Septic SOT patients display a reprogrammed immune response characterized by attenuation of hyperinflammation, preservation of innate immune competence, and coordinated immunometabolism. This immune pattern may underlie the observed survival advantage and provides a mechanistic framework for targeted therapeutic strategies in sepsis. Take Home Message: Septic patients with prior solid organ transplantation show improved 30-day survival despite chronic immunosuppression. This study provides the first comprehensive multilayer characterization of their immune response, demonstrating a reprogrammed profile with attenuated systemic inflammation, relative preservation of innate immune competence, and coordinated immunometabolism. These findings challenge the concept of global immunosuppression and suggest that distinct host-response patterns may contribute to outcome differences in sepsis.

Abstract The recently revised German Sepsis Guideline 2025 reflects an increasing integration of personalised therapy principles. This trend is observed in key recommendations relating to early recognition, anti-infective therapy, hemodynamic support, and organ-protective strategies. Early detection should be performed using validated screening instruments. Additionally, antibiotic therapy must be adapted to the individual patient, with administration ideally starting within one hour in cases of septic shock and no later than three hours in sepsis without shock. The guideline further emphasises timely diagnostics and hemodynamic stabilisation. Lactate measurement remains mandatory, while capillary refill time is additionally recommended. Norepinephrine remains the first-line vasopressor, with vasopressin as an additive option, and peripheral administration is allowed until a central venous catheter has been inserted. In parallel, the recommendations on ventilation strategies have been adjusted to optimise lung-protective management, advising a tidal volume of 6 ml/kg ideal body weight, with a range of 4–8 ml/kg in ARDS, and a driving pressure not exceeding 14 cmH2O. Prone positioning is recommended for at least 12 hours, preferably 16 hours.Regarding organ support, the guideline suggests continuous modalities of renal replacement therapy with effluent rates of 20–25 ml/kg/h, while also supporting a watchful waiting approach if urgent indications are absent. Furthermore, the scope of adjunctive therapies has been refined. High-dose vitamin C and non-specific hemoadsorption procedures are not encouraged, whereas corticosteroids are indicated in patients with persistent vasopressor requirements, preferably hydrokortisone ± fludrokortisone if feasible. Finally, the guideline highlights the importance of follow-up and prevention of post-intensive care syndrome and the establishment of structured aftercare programmes.

(1) Background: Sepsis is characterized by profound heterogeneity of immune responses, complicating biomarker-based prediction of clinical outcomes. Latent human cytomegalovirus (HCMV) infection is one of the strongest modulators of the human immune system and may influence cytokine-mediated signaling during sepsis. (2) Methods: In this post hoc analysis of 331 patients from the prospective multicenter SepsisDataNet.NRW cohort (German Clinical Trial Registry No. DRKS00018871), we quantified 13 serum cytokines on day 1 after sepsis diagnosis and determined HCMV IgG serostatus via ELISA. Using nested cross-validated logistic regression with exhaustive feature selection, we identified cytokine panels predictive of 30-day survival in the total cohort and in subgroups stratified by HCMV serostatus. (3) Results: In the total cohort, a four-cytokine panel (IL-6, IL-10, TNF-α, IL-12p70) predicted 30-day survival with a cross-validated area under the curve (AUC) of 0.66 [95% CI: 0.59–0.72]. Stratification by HCMV serostatus revealed distinct predictive profiles: in HCMV-seropositive patients, a two-cytokine model (IL-10, IL-23) achieved an AUC of 0.69 [95% CI: 0.61–0.77], whereas in seronegative patients, a model based on IL-8 and IL-17A failed to generalize (AUC = 0.47 [95% CI: 0.33–0.61]). Kaplan–Meier analysis confirmed a significant separation of survival curves for the HCMV-seropositive group (p < 0.001) but not for seronegative patients (p = 0.282). (4) Conclusions: HCMV serostatus defines an immunological context in which cytokine-based prediction of sepsis outcome becomes feasible. These data suggest that viral serostatus should be systematically incorporated into biomarker discovery and immunophenotyping approaches to improve the reproducibility and biological interpretability of sepsis endotyping.

Ventilator-associated pneumonia (VAP) remains the most frequent ICU-acquired infection and a major driver of antimicrobial exposure. Historically, clinicians treated patients for 10-14 days or longer, particularly when multidrug-resistant organisms were suspected. Current evidence from randomized trials and meta-analyses now supports shorter-course therapy (~7 days) for most immunocompetent patients with VAP who demonstrate clinical improvement. Mortality and treatment failure are not increased when compared with longer regimes. The REGARD-VAP trial demonstrated the non-inferiority of individualized ≤7-day therapy compared with conventional longer courses. This remained true even in cohorts rich in non-fermenting Gram-negative bacilli (NF-GNB) and carbapenem-resistant organisms while markedly reducing antibiotic-related toxicity. North American and European guidelines recommend 7-8 days as the default duration, with individualized extension for slow clinical response, bacteremia, uncontrolled foci, or profound immunosuppression. Additionally, biomarker-guided discontinuation, particularly serial procalcitonin (PCT), may reduce antibiotic days when used to enrich clinical assessment. This narrative review synthesizes guideline recommendations, trial evidence, biomarker-guided stewardship, and pathogen- and patient-specific scenarios to provide a practical framework for intensivists: treat until infection is controlled and the patient is improving, usually about 1 week, and extend therapy only with clear justification.

BackgroundSepsis is characterized by a dysregulated host response to infection, leading to concurrent hyperinflammation and immunosuppression, including profound alterations in T lymphocyte homeostasis. The chemokine CXCL10, an interferon-γ-inducible mediator of T cell trafficking, has been implicated in immune activation and tissue injury. However, it remains unclear whether genetic variation in CXCL10 contributes to T cell dysregulation and clinical outcomes in sepsis.MethodsIn a prospective cohort of septic patients (n=278), we analyzed CXCL10 rs8878 genotypes, circulating immune cell counts, cytokine concentrations, and CXCL10 protein and mRNA expression in whole blood. Associations between genotype, immune parameters, plasma proteomics and 30-day survival were assessed using group comparisons and Kaplan-Meier analyses. Correlation analyses were performed to evaluate relationships between CXCL10 concentrations, cytokines, and clinical parameters.ResultsVariants in the CXCL10 gene were associated with T cell dysregulation. Carriers of the rs8878 AA genotype exhibited higher circulating T cell counts and improved survival compared with G-allele carriers. Higher total and CD8+ T cell counts were significantly associated with improved survival. Among non-survivors, AA-genotype carriers showed increased CXCL10 mRNA expression, indicating genotype-dependent regulation of CXCL10 expression under conditions of fatal disease progression. CXCL10 concentrations on day 1 were positively correlated with multiple inflammatory cytokines, including IL-6, IL-8, IL-10, IL-18, MCP-1, IFN-γ, and interferon-α2, and inversely correlated with total T cell counts, supporting a link between CXCL10, systemic inflammation, and T cell depletion. No significant associations were observed between CXCL10 genotype and plasma proteomics and routine clinical parameters.ConclusionThe CXCL10 rs8878 genotype is associated with T cell dynamics and 30-day survival in sepsis, suggesting a genotype-dependent modulation of the adaptive immune response. While the AA genotype is linked to preserved T cell counts and improved outcomes, increased CXCL10 expression in non-survivors points to a context-dependent role in inflammation-driven immune dysregulation. These findings identify CXCL10 as a potential biomarker for risk stratification and a candidate target for immunomodulatory therapies in sepsis.

The recently revised German Sepsis Guideline 2025 reflects an increasing integration of personalised therapy principles. This trend is observed in key recommendations relating to early recognition, anti-infective therapy, hemodynamic support, and organ-protective strategies. Early detection should be performed using validated screening instruments. Additionally, antibiotic therapy must be adapted to the individual patient, with administration ideally starting within one hour in cases of septic shock and no later than three hours in sepsis without shock. The guideline further emphasises timely diagnostics and hemodynamic stabilisation. Lactate measurement remains mandatory, while capillary refill time is additionally recommended. Norepinephrine remains the first-line vasopressor, with vasopressin as an additive option, and peripheral administration is allowed until a central venous catheter has been inserted. In parallel, the recommendations on ventilation strategies have been adjusted to optimise lung-protective management, advising a tidal volume of 6 ml/kg ideal body weight, with a range of 4-8 ml/kg in ARDS, and a driving pressure not exceeding 14 cmH 2 O. Prone positioning is recommended for at least 12 hours, preferably 16 hours.Regarding organ support, the guideline suggests continuous modalities of renal replacement therapy with effluent rates of 20-25 ml/kg/h, while also supporting a watchful waiting approach if urgent indications are absent. Furthermore, the scope of adjunctive therapies has been refined. High-dose vitamin C and non-specific hemoadsorption procedures are not encouraged, whereas corticosteroids are indicated in patients with persistent vasopressor requirements, preferably hydrokortisone +/- fludrokortisone if feasible. Finally, the guideline highlights the importance of follow-up and prevention of post-intensive care syndrome and the establishment of structured aftercare programmes.

Background:Postoperative delirium (POD) is a frequent and serious complication in older surgical patients, characterized by acute cognitive dysfunction and fluctuating levels of consciousness. POD is associated with prolonged hospitalization, long-term cognitive decline, reduced quality of life, and increased mortality. Despite its clinical relevance, the underlying pathophysiological mechanisms remain poorly understood, and reliable biomarkers for early prediction and prevention are lacking. Objective:The CONFUSED study aims to identify molecular and clinical predictors of POD by integrating clinical data with proteomic, transcriptomic, and epigenetic analyses. The primary objective is to develop predictive models for POD using multimodal data. Secondary objectives include the identification of delirium-associated genes, proteins, and epigenetic signatures, as well as the exploration of patient subgroups at increased risk for POD. Methods:CONFUSED is a prospective observational cohort study conducted at a German university hospital. Adult patients undergoing major surgery under general anesthesia will be enrolled until 100 cases of POD have been observed, which is expected to require a total sample size of approximately 200 to 300 patients. Blood samples are collected at 4 predefined time points: before premedication, immediately after surgery, and on postoperative days 2 and 5. Samples undergo comprehensive proteomic profiling, transcriptomic analysis using RNA microarrays, DNA methylation analysis, and genotyping of selected polymorphisms. Clinical data, including demographics, comorbidities, perioperative variables, medications, and delirium assessments using the Confusion Assessment Method (CAM) and CAM for the intensive care unit, are systematically recorded. Statistical analyses include univariate and multivariate methods, as well as machine learning approaches such as random forests and support vector machines, to identify relevant biomarkers and develop predictive models. The study protocol follows STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) and TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) guidelines and was approved by the responsible ethics committees. Results:The study was registered in the German Clinical Trials Register (DRKS00033854) on March 18, 2024. Recruitment started in January 2024 and is ongoing at the time of manuscript submission. As of now, 135 patients have been enrolled. Sample collection and laboratory analyses are ongoing. Data analysis began in January 2026, with first results anticipated in July 2026. Final data lock is anticipated after the completion of recruitment. Conclusions:By integrating multimodal molecular data with clinical parameters and applying advanced machine learning techniques, the CONFUSED study aims to improve the prediction and understanding of POD. The results are expected to support the development of personalized preventive strategies and contribute to improved perioperative care for patients at risk of POD.

BackgroundSepsis, a life-threatening condition caused by a dysregulated host response to infection, remains a major cause of mortality worldwide. Identifying reliable biomarkers for prognosis and treatment is urgently needed. This study investigates the role of the Apoptosis Inhibitor of Macrophages (AIM), also known as CD5L, as a potential prognostic biomarker and therapeutic target in sepsis.MethodsWe measured free and total AIM concentrations in 90 septic patients enrolled in SepsisDataNet.NRW cohort (German Clinical Trial Registry No. DRKS00018871; http://www.sepsisdatanet.nrw). Blood samples were collected on days 1, 4, and 8, and AIM levels were quantified using ELISA. Kaplan-Meier analysis and Cox regression were performed to assess the association between AIM levels and 30-day survival. Western blot analysis was performed to detect AIM in human serum IgM and in the IgM-enriched intravenous immunoglobulin IVIG preparation Pentaglobin®.ResultsHigh total AIM concentrations (>85 ng/ml) were significantly associated with improved 30-day survival on day 1 (HR: 3.131, 95% CI: 1.629-6.019, p = 0.009), 4 (HR: 2.525, 95% CI: 1.198-5.322, p = 0.0042), and day 8 (HR: 2.317, 95% CI: 0.8565-6.266, p = 0.0457). Free AIM showed a significant association with survival only on day 8 (HR: 2.374, 95% CI: 0.8721-6.461, p = 0.0393).ConclusionTotal AIM concentration is a significant predictor of a 30-day survival in sepsis, supporting its potential use as a prognostic biomarker. Our findings also suggest that AIM may serve as a valuable prognostic biomarker and a potential target for immune-modulating therapies, including IgM-enriched intravenous immunoglobulins (IVIGs).

IntroductionRepair of mitochondrial damage seems pivotal for clinical recovery and determining outcome in patients with critical COVID-19. However, reliable biomarkers for non-invasively assessing mitochondrial repair in peripheral blood of critically ill COVID-19 patients are currently lacking. Accordingly, we sought to assess different surrogates of mitochondrial repair in peripheral blood and correlate these measurements with clinical outcome in patients with critical COVID-19.MethodsIn this prospective multicentric cohort study, 88 critically ill COVID-19 patients were enrolled across three German intensive care units. Gene products of mitochondrial quality control (MFN2, PINK, TFAM, TFB2M) and the mtDNA copy number were measured in peripheral blood mononuclear cells. Furthermore, the protein interactions between TFAM and TFB2M were quantified. Patients were stratified regarding 30-day mortality. ResultsTranscript levels of the assessed mRNA markers of mitochondrial quality control were not associated with clinical outcome. In contrast, more than 10.7 protein interactions per cell were associated with a 74% 30-day survival (37 out of 50), while 10.7 or fewer protein interactions per cell were associated with a 32% 30-day survival (12 out of 38; p < 0.001). Furthermore, multivariable Cox regression analysis revealed TFAM-TFB2M protein interaction as an independent predictor for 30-day survival (HR: 3.2; 95% CI: 1.6 to 6.5; p < 0.001). DiscussionOur findings indicate that TFAM-TFB2M protein interactions, identified as a novel biomarker, are strongly and independently associated with 30-day survival in critical COVID-19. Therefore, our data suggest a significant impact of mitochondrial repair and quality control on clinical outcome in critical COVID-19.

BACKGROUND:The heterogeneity of sepsis represents a significant challenge to the development of personalized sepsis therapies. Sepsis subtyping has therefore emerged as an important approach to this problem, but its impact on clinical practice was limited due to insufficient molecular insights. Modern proteomics techniques allow the identification of subtypes and provide molecular and mechanistical insights. In this study, we analyzed a prospective multi-center sepsis cohort using plasma proteomics to describe and characterize sepsis plasma proteome subtypes. METHODS:Plasma samples were collected from 333 patients at days 1 and 4 of sepsis and analyzed using liquid chromatography coupled to tandem mass spectrometry. Plasma proteome subtypes were identified using K-means clustering and characterized based on clinical routine data, cytokine measurements, and proteomics data. A random forest machine learning classifier was generated to showcase future assignment of patients to subtypes. RESULTS:Four subtypes with different sepsis severity were identified. Cluster 0 represented the most severe form of sepsis, with 100% mortality. Cluster 1, 2 and 3 showed a gradual decrease of the median SOFA score, as reflected by clinical data and cytokine measurements. At the proteome level, the subtypes were characterized by distinct molecular features. We observed an alternating immune response, with cluster 1 showing prominent activation of the adaptive immune system, as indicated by elevated levels immunoglobulin (Ig) levels, which were verified using orthogonal measurements. Cluster 2 was characterized by acute inflammation and the lowest Ig levels. Cluster 3 represented the sepsis proteome baseline of the investigated cohort. We generated an ML classifier and optimized it for the minimum number of proteins that could realistically be implemented into routine diagnostics. The model, which was based on 10 proteins and Ig quantities, allowed the assignment of patients to clusters 1, 2 and 3 with high confidence. CONCLUSION:The identified plasma proteome subtypes provide insights into the immune response and disease mechanisms and allow conclusions on appropriate therapeutic measures, enabling predictive enrichment in clinical trials. Thus, they represent a step forward in the development of targeted therapies and personalized medicine for sepsis.

BACKGROUND:Sepsis remains a leading cause of mortality in intensive care units. Understanding the dynamics of the plasma proteome of patients with sepsis is critical for improving prognostic and therapeutic strategies. METHODS:This prospective, multicentre observational cohort study included 363 patients with sepsis recruited from five university hospitals in Germany between March 2018 and April 2023. Plasma samples were collected on days 1 and 4 after sepsis diagnosis, and proteome analysis was performed using mass spectrometry. Classical statistical methods and machine learning (random forest) were employed to identify proteins associated with 30-day survival outcomes. FINDINGS:Out of 363 patients, 224 (62%) survived, and 139 (38%) did not survive the 30-day period. Proteomic analysis revealed significant differences in 87 proteins on day 1 and 95 proteins on day 4 between survivors and non-survivors. Additionally, 63 proteins were differentially regulated between day 1 and day 4 in the two groups. The identified protein networks were primarily related to blood coagulation, immune response, and complement activation. The random forest classifier achieved an area under the receiver operating characteristic curve of 0.75 for predicting 30-day survival. The results were compared and partially validated with an external sepsis cohort. INTERPRETATION:This study describes temporal changes in the plasma proteome associated with mortality in sepsis. These findings offer new insights into sepsis pathophysiology, emphasizing the innate immune system as an underexplored network, and may inform the development of targeted therapeutic strategies. FUNDING:European Regional Development Fund of the European Union. The State of North Rhine-Westphalia, Germany.

The glucocorticoid receptor (GR), particularly its isoforms GRα and GRβ, plays a crucial role in modulating inflammatory responses. The rs6198 single nucleotide polymorphism (SNP) in the NR3C1 gene, which encodes GR, has been associated with adverse outcomes in various diseases due to its potential effect on GR isoform expression. This study aims to explore the impact of the rs6198 SNP in sepsis. Specifically, we tested the hypothesis that the presence of a particular genotype of the rs6198 SNP is associated with an increased 30-day mortality rate in patients with sepsis. This prospective, multicenter study included 204 ICU patients diagnosed with sepsis, as part of the Sepsis.Data.Net NRW cohort. Genotyping for rs6198 and immunofluorescence as well as quantification of GR expression were performed. Statistical analyses included Hardy-Weinberg equilibrium, Kaplan-Meier survival analysis, log-rank tests, multivariate Cox regression, and logistic regression. Genotyping for the rs6198 SNP identified 137 patients (67%) with the TT- and 67 (33%) with CC/CT-genotype. Patients with the TT-genotype had a 30-day survival rate of 65% (89 of 137 patients), which was significantly lower than the 82% survival rate (55 of 67 patients) observed in the patients with the CC/CT-genotype (p = 0.006). A multivariate Cox regression analysis, adjusted for age, SOFA and SAPS2 score, and selected laboratory values, revealed that the TT-genotype was independently associated with an increased risk of death (HR 3.56, 95% CI 1.22-10.38, p = 0.02). Subgroup analysis demonstrated a particularly pronounced impact among patients with initially high disease severity (HR 6.16, 95% CI 1.66-22.80, p = 0.007). In addition, expression analysis revealed a significantly higher presence of GRα in patients with the TT-genotype compared to those with CC/CT genotype (p = 0.023). Increased GRα expression was also associated with higher 30-day mortality (HR 2.38, 95% CI 1.48-3.82, p < 0.001). The rs6198 SNP in the NR3C1 gene is associated with 30-day mortality in sepsis patients and correlates with increased expression of the GRα isoform. These results highlight the TT-genotype as a potential risk marker. Further research is needed to clarify the causal mechanisms and explore personalized therapeutic implications in sepsis management.

The SARS-CoV-2 pandemic led to significant advancements in treatment and vaccination, contributing to a decline in overall COVID-19-related mortality. However, it remains unclear whether the mortality rate for critical cases treated on intensive care units has also decreased. This multicentric, multinational retrospective observational study analyzed 447 critically ill COVID-19 patients treated on ICUs across ten study centers in Germany and Austria. Patients were categorized into two periods: period 1 (March 2020 to May 2021, n = 316) and period 2 (June 2021 to January 2022, n = 131). Despite evolving treatment strategies and widespread vaccine availability in period 2, 30-day mortality remained unchanged (30% in period 1 vs. 37% in period 2; HR 1.26, 95% CI: 0.90–1.79, p = 0.181). Further outcomes, including ICU-free days (p = 0.735), ventilatory support-free days (p = 0.699), vasopressor-free days (p = 0.379), and dialysis-free days (p = 0.396), also showed no significant differences. Notably, 81% (106 of 131) of ICU patients in period 2 were unvaccinated, underscoring the persistent vulnerability of this group. These findings suggest that while public health measures reduced overall COVID-19 severity, critical illness remained highly lethal. Further research is needed to explore targeted interventions for high-risk ICU patients and to better understand the factors contributing to persistent mortality despite medical advancements.

Airway management is a core competency in anesthesiology that has significantly evolved in recent years, primarily due to technological innovations. The 2023 update of the S1 guideline on airway management, published by the German Society for Anesthesiology and Intensive Care Medicine (DGAI), offers evidence-based insights into these advancements and provides clear recommendations for clinical practice. More than a theoretical update, the guideline serves as a practical resource for bedside care, addressing a broad spectrum of innovations and clarifications while leaving few questions unanswered. This review article summarizes the key updates and their practical implementation.

INTRODUCTION:An increasing amount of longitudinal health data is available on critically ill septic patients in the age of digital medicine, including daily sequential organ failure assessment (SOFA) score measurements. Thus, the assessment in sepsis focuses increasingly on the evaluation of the individual disease's trajectory. Machine learning (ML) algorithms may provide a promising approach here to improve the evaluation of daily SOFA score dynamics. We tested whether ML algorithms can outperform the conventional ΔSOFA score regarding the accuracy of 30-day mortality prediction.METHODS:We used the multicentric SepsisDataNet.NRW study cohort that prospectively enrolled 252 sepsis patients between 03/2018 and 09/2019 for training ML algorithms, i.e. support vector machine (SVM) with polynomial kernel and artificial neural network (aNN). We used the Amsterdam UMC database covering 1,790 sepsis patients for external and independent validation.RESULTS:Both SVM (AUC 0.84; 95% CI: 0.71-0.96) and aNN (AUC 0.82; 95% CI: 0.69-0.95) assessing the SOFA scores of the first seven days led to a more accurate prognosis of 30-day mortality compared to the ΔSOFA score between day 1 and 7 (AUC 0.73; 95% CI: 0.65-0.80; p = 0.02 and p = 0.05, respectively). These differences were even more prominent the shorter the time interval considered. Using the SOFA scores of day 1 to 3 SVM (AUC 0.82; 95% CI: 0.68 0.95) and aNN (AUC 0.80; 95% CI: 0.660.93) led to a more accurate prognosis of 30-day mortality compared to the ΔSOFA score (AUC 0.66; 95% CI: 0.58-0.74; p < 0.01 and p < 0.01, respectively). Strikingly, all these findings could be confirmed in the independent external validation cohort.CONCLUSIONS:The ML-based algorithms using daily SOFA scores markedly improved the accuracy of mortality compared to the conventional ΔSOFA score. Therefore, this approach could provide a promising and automated approach to assess the individual disease trajectory in sepsis. These findings reflect the potential of incorporating ML algorithms as robust and generalizable support tools on intensive care units.

Sepsis is a common life-threatening disease caused by dysregulated immune response and metabolic acidosis which lead to organ failure. An abnormal expression of aquaporins plays an important role in organ failure. Additionally, genetic variants in aquaporins impact on the outcome in sepsis. Thus, we investigated the polymorphism (rs17553719) and expression of aquaporin-3 (AQP3) and correlated these measurements with the survival of sepsis patients. Accordingly, we collected blood samples on several days (plus clinical data) from 265 sepsis patients who stayed in different ICUs in Germany. Serum plasma, DNA, and RNA were then separated to detect the promotor genotypes of AQP3 mRNA expression of AQP3 and several cytokines. The results showed that the homozygote CC genotype exhibited a significant decrease in 30-day survival (38.9%) compared to the CT (66.15%) and TT genotypes (76.3%) (p = 0.003). Moreover, AQP3 mRNA expression was significantly higher and nearly doubled in the CC compared to the CT (p = 0.0044) and TT genotypes (p = 0.018) on the day of study inclusion. This was accompanied by an increased IL-33 concentration in the CC genotype (day 0: p = 0.0026 and day 3: p = 0.008). In summary, the C allele of the AQP3 polymorphism (rs17553719) shows an association with increased AQP3 expression and IL-33 concentration accompanied by decreased survival in patients with sepsis.

Background Metabolic derangements in sepsis stem from mitochondrial injury and contribute to organ dysfunction and mortality. Thus, repair of mitochondrial damage seems pivotal for recovery and determining clinical outcome in sepsis. However, reliable biomarkers assessing mitochondrial repair noninvasively in peripheral blood are currently lacking. Research Question Are different gene transcripts related to mitochondrial repair (ie, biogenesis, fusion, fission, mitophagy) and the protein interaction assessing mitochondrial biogenesis, both measured in peripheral blood, associated with disease severity and clinical outcome? Study Design and Methods Healthy control patients (n = 22), uninfected critically ill control patients (n = 13), and patients with sepsis (n = 75) were included in this prospective multicentric observational study. Gene products of mitochondrial quality control and mitochondrial DNA were measured on day 1 and 4 in peripheral blood mononuclear cells. In addition, we assessed in the same samples the mitochondrial protein interaction of mitochondrial transcription factor A (TFAM)-mitochondrial transcription factor B2 (TFB2M) using a proximity ligation assay. Patients with sepsis were stratified in the outcome-related subgroups ICU-free within 1 week (n = 16), not ICU-free within 1 week (n = 36), and 30-day nonsurvivors (n = 23). Results Transcript levels of the assessed messenger RNA markers of patients with sepsis were not associated with disease severity nor did they predict clinical outcome. Strikingly, the mitochondrial protein interaction of TFAM-TFB2M on day 4 (P < .05) and the difference between day 1 and 4 (P < .001) allowed stratification in the three clinical outcome subgroups. In addition, a decline in TFAM-TFB2M protein interactions between day 1 and 4 was an independent predicator for 30-day mortality (adjusted hazard ratio, 8.34; 95% CI, 2.73-25.45; P < .001). Interpretation Patients with sepsis with an early activation of mitochondrial biogenesis were more likely to be ICU-free within 1 week. A mitochondrial and clinical recovery can be assessed via the protein interaction of TFAM-TFB2M in peripheral blood. Thus, mitochondrial protein interactions targeting mitochondrial biogenesis provide a promising dimension of novel biomarkers assessing mitochondrial dysfunction in sepsis.

The variability in mortality in sepsis could be a consequence of genetic variability. The glucocorticoid system and the intermediate TSC22D3 gene product—glucocorticoid-induced leucine zipper—are clinically relevant in sepsis, which is why this study aimed to clarify whether TSC22D3 gene polymorphisms contribute to the variance in sepsis mortality. Blood samples for DNA extraction were obtained from 455 patients with a sepsis diagnosis according to the Sepsis-III criteria and from 73 control subjects. A SNP TaqMan assay was used to detect single-nucleotide polymorphisms (SNPs) in the TSC22D3 gene. Statistical and graphical analyses were performed using the SPSS Statistics and GraphPad Prism software. C-allele carriers of rs3747406 have a 2.07-fold higher mortality rate when the sequential organ failure assessment (SOFA) score is higher than eight. In a multivariate COX regression model, the SNP rs3747406 with a SOFA score ≥ 8 was found to be an independent risk factor for 30-day survival in sepsis. The HR was calculated to be 2.12, with a p-value of 0.011. The wild-type allele was present in four out of six SNPs in our cohort. The promoter of TSC22D3 was found to be highly conserved. However, we discovered that the C-allele of rs3747406 poses a risk for sepsis mortality for SOFA Scores higher than 6.

Sepsis involves an immunological systemic response to a microbial pathogenic insult, leading to a cascade of interconnected biochemical, cellular, and organ–organ interaction networks. Potential drug targets can depict aquaporins, as they are involved in immunological processes. In immune cells, AQP3 and AQP9 are of special interest. In this study, we tested the hypothesis that these aquaporins are expressed in the blood cells of septic patients and impact sepsis survival. Clinical data, routine laboratory parameters, and blood samples from septic patients were analyzed on day 1 and day 8 after sepsis diagnosis. AQP expression and cytokine serum concentrations were measured. AQP3 mRNA expression increased over the duration of sepsis and was correlated with lymphocyte count. High AQP3 expression was associated with increased survival. In contrast, AQP9 expression was not altered during sepsis and was correlated with neutrophil count, and low levels of AQP9 were associated with increased survival. Furthermore, AQP9 expression was an independent risk factor for sepsis lethality. In conclusion, AQP3 and AQP9 may play contrary roles in the pathophysiology of sepsis, and these results suggest that AQP9 may be a novel drug target in sepsis and, concurrently, a valuable biomarker of the disease.

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