Daily Sepsis Research Analysis

Haptoglobin (Hp) scavenges cell-free hemoglobin and correlates with the prognosis of human sepsis, a life-threatening systemic inflammatory condition. Despite extensive research on Hp glycosylation as a glyco-biomarker for cancers, understanding glycosylated modifications of Hp in sepsis patients (SPs) remains limited. Our study reveals elevated levels of terminal fucosylation at Asn207 and Asn211 of Hp in SP plasma, along with heightened inflammatory responses, compared to healthy controls (trial registration NCT05911711). Fucosylated (Fu)-Hp purified from SPs upregulates inflammatory cytokines and chemokines, along with NLRP3 inflammasome activation. Single-cell RNA sequencing identifies a distinct macrophage-like cell population with increased expressions of inflammatory mediators and FUT4 in response to Fu-Hp. Additionally, Mincle, a C-type lectin receptor, interacts with Fu-Hp to amplify the inflammatory responses and signaling. Moreover, the Hp fucosylation (AAL) level significantly correlates with the levels of inflammatory cytokines in sepsis patients, suggesting that Fu-Hp is clinically relevant. Finally, Fu-Hp treatment significantly enhances the levels of inflammatory cytokines in the plasma and various tissues of mice. Together, our findings reveal a role of Fu-Hp, derived from sepsis patients, in driving inflammation, and suggest that targeting Fu-Hp could serve as a promising intervention for combating sepsis. Trial registration NCT05911711.

BACKGROUND: The application of sepsis subtypes to enhance personalized medicine in critically ill patients is hindered by the lack of validation across diverse cohorts and the absence of a simple classification model. We aimed to validate the previously identified SENECA clinical sepsis subtypes in multiple large ICU cohorts, and to develop parsimonious classifier models for δ-type adjudication in clinical practice. METHODS: Data from four cohorts between 2008 and 2023 were used to assign α, β, γ and δ-type in patients fulfilling the Sepsis-3 criteria using clinical variables: (I) The Molecular diAgnosis and Risk stratification of Sepsis (MARS, n = 2449), (II) a contemporary continuation of the MARS study (MARS2, n = 2445) (III) the Dutch National Intensive Care Evaluation registry (NICE, n = 28,621) and (IV) the Medical Information Mart for Intensive Care including (MIMIC-IV, n = 18,661). K-means clustering using clinical variables was conducted to assess the optimal number of classes and compared to the SENECA subtypes. Parsimonious models were built in the SENECA derivation cohort to predict subtype membership using logistic regression, and validated in MARS and MIMIC-IV. RESULTS: Among 52.226 patients with sepsis, the subtype distribution in MARS, MARS2 and NICE was 2-6% for the α-type, 1-5% for the β-type, 49-65% for the γ-type and 26-48% for the δ-type compared to 33%, 27%, 27% and 13% in the original SENECA derivation cohort, whereas subtype distribution in MIMIC-IV was more similar at 25%, 24%, 27% and 25%, respectively. In-hospital mortality rates were significantly different between the four cohorts for α, γ and δ-type (p < 0.001). Method-based validation showed moderate overlap with the original subtypes in both MARS and MIMIC-IV. A parsimonious model for all four subtypes had moderate to low accuracy (accuracy 62.2%), while a parsimonious classifier model with 3 variables (aspartate aminotransferase, serum lactate, and bicarbonate) had excellent accuracy in predicting the δ-type patients from all other types in the derivation cohort and moderate accuracy in the validation cohorts (MARS: area under the receiver operator characteristic curve (AUC) 0.93, 95% CI [0.92-0.94], accuracy 85.5% [84.0-86.8%]; MIMIC-IV: AUC 0.86 [0.85-0.87], accuracy 82.9% [82.4-83.4%]). CONCLUSIONS: The distribution and mortality rates of clinical sepsis subtypes varied between US and European cohorts. A three-variable model could accurately identify the δ-type sepsis patients.

BACKGROUND: Skin antisepsis is one of the most important bundle measures to decrease central line-related bloodstream infections (CRBSIs). However, in the neonatal population, the use of alcoholic chlorhexidine is limited by the risk of skin lesions. OBJECTIVE: We hypothesised that skin antisepsis with alcohol-based 2% chlorhexidine instead of aqueous 2% chlorhexidine could reduce the incidence of CRBSI without increasing skin complications. DESIGN: We conducted a double cohort study comparing two periods of 3 years, first using aqueous and second using alcohol-based chlorhexidine, leaving a 1-year washout interval between them. In extremely preterm infants, aqueous chlorhexidine was used during the first week of life in both periods. RESULTS: A total of 1783 patients and 2493 episodes of central line catheter were analysed. There were no statistically significant differences in clinical and demographic data from infants in both periods. There was a significant reduction in the pooled incidence density of CRBSI in the second compared with the first period (4.03 vs 9.05 episodes/1000 central line days, OR 0.45 (95% CI 0.29 to 0.68)). The overall absolute risk reduction was 0.039 (95% CI 0.023 to 0.056) and the number needed to treat was 25. A similar but not significant reduction of the small number of CRBSI was observed in extremely preterm infants within the first week of life OR 0.43 (95% CI 0.134 to 1.379). No statistically significant differences in skin lesions were observed between periods, making erythema the most common injury(5.1% vs 4.2%). RELEVANCE: Alcohol-based 2% chlorhexidine as a skin antiseptic could reduce the incidence of CRBSI in neonates without producing an increase in skin lesions.