Daily Sepsis Research Analysis

Sepsis-associated acute lung injury (S-ALI) represents a significant clinical challenge due to its high incidence and mortality rates. Macrophages play a central and dual role in the pathogenesis of S-ALI, they serve as a critical component of the innate immune defense against pathogen invasion, while simultaneously contributing to the propagation of excessive inflammatory responses and tissue damage. Consequently, modulation of macrophage function has emerged as a promising therapeutic strategy for S-ALI. Accumulating evidence indicates that heme oxygenase-1 (HO-1, encoded by HMOX1) exerts endogenous protective effects in S-ALI. Our prior studies demonstrated that HO-1 ameliorates S-ALI by modulating oxidative stress in macrophages. Furthermore, emerging reports suggest that HO-1 may also mitigate this pathological process through regulation of Golgi stress; however, the underlying molecular mechanisms remain poorly defined. In this study, using both in vivo and in vitro models of S-ALI, we demonstrate that HO-1 in alveolar macrophages directly interacts with the transcriptional activation domain (TAD) of CREB3, leading to the degradation of the CREB3/ARF4 signaling pathway. Moreover, activated CREB3 suppresses HO-1 gene transcription, establishing a negative feedback regulatory loop. This mechanism effectively restricts CREB3 trafficking from the endoplasmic reticulum to the Golgi apparatus and its subsequent nuclear translocation, thereby preventing excessive activation of CREB3-dependent signaling pathways during S-ALI and attenuating Golgi stress. Additionally, clinical analyzes reveal that the expression levels of HO-1, CREB3, and ARF4 in peripheral blood mononuclear cells (PBMCs) from sepsis patients are significantly elevated compared to those in non-septic controls and positively correlate with APACHE II and SOFA scores. These markers demonstrate significant positive associations with established severity indices, suggesting that HO-1, CREB3, and ARF4-either individually or in combination-may serve as potential novel biomarkers for the diagnosis of sepsis, the assessment of disease severity, and the prediction of clinical outcomes. Collectively, these findings indicate that HO-1 alleviates Golgi stress in macrophages by inhibiting the CREB3/ARF4 axis, thus improving cellular functional homeostasis, and highlight their potential as both a diagnostic biomarker and a therapeutic target in sepsis.

BACKGROUND Sepsis is a critical condition requiring prompt identification and intervention, especially in prehospital settings where diagnostic uncertainty is high. This study investigated the effectiveness of a dual-marker approach using end-tidal carbon dioxide (ETCO2) and lactate levels for early sepsis detection. MATERIAL AND METHODS In this single-center prospective cohort study, we enrolled 327 patients with suspected sepsis admitted through prehospital emergency care from January 2023 to January 2025. We evaluated the diagnostic performance of ETCO₂ and lactate, using thresholds of ETCO₂ ≤25 mmHg and ≤30 mmHg, and hyperlactatemia defined as ≥2 mmol/L. Primary outcomes were sepsis and septic shock diagnosis, while secondary outcomes included ICU admission and in-hospital mortality. Receiver operating characteristic (ROC) curves were used to assess diagnostic accuracy. RESULTS Our findings revealed that lower prehospital ETCO₂ and elevated lactate levels were significantly associated with increased risks of septic shock and in-hospital mortality. ETCO₂ ≤25 mmHg alone showed an AUC of 0.781 (95% CI 0.738-0.846) for sepsis, with a sensitivity of 82.9% and specificity of 81.7%. The combined model of ETCO₂ ≤25 mmHg and hyperlactatemia significantly enhanced diagnostic accuracy, achieving a sensitivity of 89.9% and specificity of 91.7%. CONCLUSIONS The integration of ETCO₂ and lactate as a dual-marker decision rule significantly enhances early sepsis detection in prehospital settings, surpassing the limitations of single-biomarker or symptom-based approaches. This dual-marker approach offers a robust, objective tool for improving sepsis risk stratification, potentially leading to better patient outcomes through timely intervention.

It is challenging to reduce time to optimal antimicrobial therapy in patients with sepsis for microbiology laboratories in low to middle-income countries. We evaluated the diagnostic accuracy and impact of a diagnostic stewardship bundle titled "Sepsis-24" to reduce turnaround time (TAT) of provisional blood culture reports (pBCR) ≤ 24 h in patients with gram-negative bacteraemia. During the preintervention period (January-May 23), the key preanalytical and analytical parameters of automated blood culture diagnostics were optimized in a multiphasic manner. Early microbial identification and susceptibility testing were performed by direct inoculation of VITEK-2 identification cards from flagged blood culture bottles (+ BCs) and EUCAST RAST method, read at 8-hour. During the intervention period (June-December 2023), Sepsis-24 was implemented in adult ICUs to provide pBCR for four RAST reportable gram-negatives (RRGNs). The agreements of direct microbial identification and RAST for tested drug-bug combinations were 94% [95%CI: 90-98] and 93% [95%CI: 91-94], respectively during both periods. There was a statistically significant reduction in BC loading, unloading and performance of direct VITEK/RAST from + BC during intervention period [median (minutes): 32 versus 25, 12 versus 2, and 181 versus 70, p ≤ 0.001, respectively]. Of 49 pBCRs released, 48 (98%) were concordant in species-level microbial identification with a median TAT of 1473 min [IQR: 1635 - 1321], from sample receiving. Sepsis-24 facilitated early review of antimicrobial regimen in 71% (34/48) patients leading to therapy change in 64.7% (22/34) patients. Sepsis-24 was found to be diagnostically accurate and facilitated early review of antimicrobial therapy in our resource-limited setting.