Daily Sepsis Research Analysis

BACKGROUND: Sepsis survivors who develop recurrent or secondary infections often exhibit prolonged immunosuppression and impaired pathogen clearance, yet the underlying mechanisms remain poorly defined and targeted therapies are limited. METHODS: We established a murine second-hit sepsis model to examine immune remodeling during the immunosuppressive phase after an initial inflammatory insult. Bone marrow immune remodeling was characterized by flow cytometry and single-cell RNA sequencing. Purified myeloid subsets were subjected to functional assays, transcriptomic analyses, and molecular studies to define how Slfn4 regulates the suppressive program of monocytic myeloid-derived suppressor cell-like (M-MDSC-like) cells. RESULTS: We found that Slfn4 marks an immunosuppressive M-MDSC-like subset in the bone marrow during second-hit sepsis, and our data support a role for the Slfn4-Stat3 axis in maintaining its suppressive phenotype. Genetic silencing of Slfn4 or pharmacologic inhibition of Stat3 was associated with reduced M-MDSC-like cell abundance, partially restored T-cell function, and improved survival. Mechanistically, our data supports a model in which SLFN4 enhances Stat3 activation in association with post-transcriptional repression of Socs3, potentially through interaction with an AU-rich element within the Socs3 3'-UTR. In addition, sildenafil, a PDE5 inhibitor, decreased M-MDSC-like cell abundance and enhanced bacterial clearance in vivo. CONCLUSIONS: These findings implicate the Slfn4-Stat3 axis in bone marrow-associated immunosuppression in this murine second-hit sepsis model and support further investigation of this pathway in the late immunosuppressive phase of sepsis.

IMPORTANCE: Although the Phoenix sepsis criteria were developed from international cohorts, their performance in mortality prediction and feasibility for routine electronic health record (EHR) applications have been understudied outside of pediatric intensive care units and high-income settings outside of the US. OBJECTIVE: To validate the Phoenix criteria's mortality prediction performance against other severity scores, and to evaluate the feasibility of using routine EHR data for identifying pediatric sepsis across the full spectrum of hospital care. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed pediatric hospitalizations between April 1, 2009, and March 31, 2024, at 36 publicly funded hospitals in Hong Kong, China. The cohort included children 28 days to younger than 18 years of age with presumed infection. Hong Kong's population-based EHR-Clinical Data Analysis and Reporting System (CDARS)-was the source of inpatient and outpatient clinical data, including demographic characteristics, medication records, and laboratory and microbiological results. EXPOSURE: The Phoenix-8 criteria were used primarily, defining sepsis as a score of 2 or higher and uncomplicated infection as a score lower than 2. Other severity scores-Phoenix-4, pediatric Sequential Organ Failure Assessment (pSOFA), and Pediatric Logistic Organ Dysfunction version 2 (PELOD-2)-were also calculated. MAIN OUTCOMES AND MEASURES: Performance of Phoenix-8 criteria and comparator severity scores for all-cause hospital mortality was assessed by area under the precision recall curve (AUPRC), area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. Availability of EHR data within the CDARS was determined for score calculation. RESULTS: Among 140 633 patients with presumed infection (median [IQR] age, 4.0 [1.0-8.0] years; 77 665 males [55.2%]), 7547 (5.4%; 95% CI, 5.2%-5.5%) met the Phoenix-8 criteria for sepsis; 133 086 patients (94.6%; 95% CI, 94.5%-94.8%) were classified as having uncomplicated infection. Patients who met the Phoenix-8 criteria had higher mortality (4.5% [95% CI, 4.0%-5.0%; n = 337] vs 0.1% [95% CI, 0.1%-0.1%; n = 114]; P < .001) than patients with uncomplicated infection. Phoenix-8 demonstrated an AUPRC of 0.27 (95% CI, 0.23-0.32) and an AUROC of 0.91 (95% CI, 0.89-0.93) for mortality, outperforming pSOFA (AUPRC: 0.15 [95% CI, 0.12-0.19]; AUROC: 0.80 [95% CI, 0.78-0.83]), but not Phoenix-4 (AUPRC: 0.23 [95% CI, 0.19-0.27]; AUROC: 0.90 [95% CI, 0.88-0.91]) or PELOD-2 (AUPRC: 0.29 [95% CI, 0.24-0.33]; AUROC: 0.89 [95% CI, 0.87-0.91]). Mean data availability for variables required in score calculation was 50.7% (95% CI, 50.6%-50.7%) for pSOFA, 43.3% (95% CI, 43.2%-43.4%) for Phoenix-8, 38.7% (95% CI, 38.6%-38.7%) for PELOD-2, and 28.6% (95% CI, 28.5%-28.7%) for Phoenix-4. CONCLUSIONS AND RELEVANCE: In this cohort study of hospitalized patients with presumed infection in Hong Kong, the Phoenix criteria effectively identified patients at high risk of death across the full spectrum of inpatient care and offered the most favorable balance of mortality discrimination and data availability among the severity scores evaluated. These findings support the generalizability of the Phoenix-8 criteria for pediatric sepsis identification across international settings.

OBJECTIVE: Although inappropriate therapy has been consistently associated with adverse outcomes, the magnitude and consistency of the benefit associated with appropriate empiric therapy in critically ill patients remain uncertain. We aimed to quantify the prevalence of appropriate empiric antimicrobial therapy and evaluate its association with outcomes and antimicrobial exposure in a large international ICU cohort. METHODS: This predefined sub-analysis of the DIANA study included adult ICU patients receiving empirical antimicrobials for suspected or confirmed bacterial infection. Only patients with microbiologically confirmed infections were analyzed, and therapy was classified as appropriate if at least one agent demonstrated in vitro activity against the identified pathogen. Associations with 28-day mortality and antimicrobial-free days were assessed using multivariable logistic and Cox regression models. Pre-specified interaction analyses explored effect modification by disease severity and diagnostic certainty. RESULTS: Of 845 patients with microbiologically confirmed infections, 87.7% received appropriate empirical antimicrobial therapy. Compared with inappropriate therapy, appropriate therapy was associated with significantly lower ICU mortality and longer 28-day antimicrobial-free days and mechanical ventilation-free days. After multivariable adjustment, appropriate therapy remained independently associated with reduced 28-day mortality [adjusted odds ratio (OR) 1.83, 95% confidence interval 1.11-3.06, p = 0.02; hazard ratio (HR) 1.51, 95% CI 1.03-2.21, p = 0.035]. Effect-modification analyses demonstrated that the survival benefit of appropriate therapy was consistent across levels of diagnostic certainty and was most pronounced in patients with moderate illness severity (SOFA 3-9). CONCLUSION: In critically ill ICU patients, appropriate empirical antimicrobial therapy is independently associated with reduced 28-day mortality rates.