Daily Sepsis Research Analysis

IMPORTANCE: Epstein-Barr virus (EBV) seropositivity is associated with chronic immune dysregulation conditions, including multiple sclerosis, systemic lupus erythematosus, post-COVID-19 condition, and multiple cancers. Sepsis is an acute immune dysregulation condition attributed to 1 of 5 global deaths. OBJECTIVE: To assess causal associations among EBV seropositivity, immune dysregulation, and mortality in children with sepsis. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed 320 children with sepsis in the 9-center Eunice Kennedy Shriver National Institutes of Child Health and Development Collaborative Pediatric Critical Care Research Network Phenotyping Pediatric Sepsis-Induced Multiple Organ Failure (PHENOMS) study who had not previously received intravenous immune globulin. Blood samples and clinical data were collected from January 1, 2015, to December 31, 2018, and assayed from January 1, 2019, to December 31, 2022. Causal algorithms were modeled in directed acyclic graphs and subsequent sensitivity and mediation analyses applied with further confirmation by structural equation modeling. Data analysis was performed from May 2022 to January 2025. INTERVENTION: Blood sample collected at 24 to 48 hours of sepsis. MAIN OUTCOMES AND MEASURES: Circulating biomarkers of inflammation (C-reactive protein, ferritin, and 32 cytokines), immune depression (ex vivo tumor necrosis factor response to endotoxin < 200 pg/mL), thrombotic microangiopathy (ADAMTS13 activity <57%), and EBV seropositivity (viral capsid IgG) were measured. Causal inference analysis identified causal associations between EBV seropositivity, immune dysregulation biomarkers, macrophage activation syndrome, and death. RESULTS: Of the 320 children (median [IQR] age, 6 [1-12] years; 172 [53.8%] male), 150 (46.9%) were previously healthy, and 72 (22.5%) had immunocompromise at admission. A total of 172 (53.8%) had causal associations with death directly and through the mediators hyperferritinemia and macrophage activation syndrome (MAS) and also had direct causal associations with increased C-reactive protein, ferritin, and interleukin 18 binding protein, which in turn had direct causal associations with decreased ADAMTS 13 activity and decreased whole blood ex vivo tumor necrosis factor response to endotoxin. Mediation analysis found that EBV seropositivity was associated with mortality (estimate [SE], 1.86 [0.55]; P < .001). With both EBV seropositivity and ferritin included in the model, the effect of EBV seropositivity on death remained (estimate [SE], 1.52 [0.57]; P = .007), as did the ferritin effect (estimate [SE], 0.50 [0.15]; P = .001). EBV seropositivity remained significantly associated with death even after adjustment for MAS (estimate [SE], 1.78 [0.56]; P = .001). CONCLUSIONS AND RELEVANCE: In this cohort study of pediatric sepsis, EBV seropositivity was associated with immune dysregulation and mortality. Further study is warranted to address the possibility that latent EBV infection immune reprogramming poses an important public health problem that contributes to not only chronic disorders of immune dysregulation but also acute disorders of immune dysregulation, such as sepsis.

PURPOSE: This is the third of three parts of the clinical practice guideline from the European Society of Intensive Care Medicine (ESICM) on fluid management in adult critically ill patients. This part addresses fluid removal in the de-escalation phase of shock management. METHODS: This guideline was formulated by an international panel of clinical experts, methodologists, and patient representatives. A literature search was conducted to identify relevant randomized controlled trials (RCTs) in adults published up to February 2025. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was applied to evaluate the certainty of evidence and to move from evidence to decision. RESULTS: Based on data from 13 RCTs, the panel issued three conditional recommendations. The panel suggested de-escalation of fluid therapy over no de-escalation in critically ill adults after the acute phase of fluid resuscitation (low certainty evidence). They suggested protocolized fluid removal by diuretics over usual care in critically ill patients after the acute phase of fluid resuscitation (moderate certainty evidence). A conditional recommendation was issued against the routine use of ultrafiltration or extracorporeal fluid removal in critically ill adults after the acute phase of fluid resuscitation, without other indication for RRT (low certainty evidence). There was limited evidence to comment on fluid removal in specific patient cohorts. CONCLUSIONS: This ESICM guideline provides three recommendations to inform clinicians on fluid removal during the de-escalation phase in critically ill patients with shock who no longer need fluid resuscitation.

M1 macrophage polarization plays a key role in the onset and progression of sepsis. Fibroblast growth factor 15 (FGF15) suppresses septic inflammation through its FGF receptor 4 (FGFR4); however, the underlying mechanisms are largely unclear. In this study, we evaluated the anti-inflammatory effects of recombinant FGF15 (rFGF15) in cecal ligation and puncture (CLP)-induced septic mice in vivo, as well as lipopolysaccharide (LPS)-stimulated mouse bone marrow-derived macrophages (BMDMs) and RAW264.7 macrophages in vitro. We observed that rFGF15 suppressed M1 macrophage polarization and associated inflammatory responses in both CLP-induced septic mice and LPS-stimulated BMDMs and RAW264.7 macrophages. Additionally, macrophage-depleted CLP mice transplanted with LPS-stimulated BMDMs pre-treated with rFGF15 exhibited reduced multi-organ inflammation and enhanced survival compared to those receiving LPS-stimulated BMDMs without rFGF15 treatment. Mechanistically, FGF15 activated the neurofibromin 2 (NF2)-Hippo pathway through FGFR4, leading to the inhibition of glycolysis, lactate production, and histone H3K18 lactylation. This led to reduced expression of interferon regulatory factor 7 (Irf7), a key regulator of type I interferon responses. In conclusion, FGF15 suppresses M1 macrophage polarization and associated inflammatory responses in sepsis by activating the NF2-Hippo pathway, thereby inhibiting H3K18 lactylation-driven Irf7 expression. FGF15 holds promise as a potential innovative therapy for sepsis.