Daily Sepsis Research Analysis

BACKGROUND: Early discontinuation of empirical antibiotics in adults with high-risk febrile neutropenia based on clinical stability and defervescence, irrespective of neutrophil count, has been shown to reduce antibiotic exposure without compromising safety. We aimed to evaluate this approach in children with cancer, a population for which randomised trials in high-income settings are lacking. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised, superiority trial in three paediatric haematology-oncology centres in Denmark. Patients aged 0-17 years receiving intensive chemotherapy and presenting with fever during high-risk neutropenia (absolute neutrophil count <0·5 × 10 FINDINGS: Between Nov 26, 2020, and Jan 28, 2025, febrile episodes were systematically screened for eligibility; 88 febrile episodes in 70 children were randomly assigned (45 to the short treatment group and 43 to the long treatment group) and included in the intention-to-treat analysis. 37 (42%) episodes were in female participants and 51 (58%) were in male participants. The time on antibiotic treatment within the 28-day follow-up was a mean of 8·1 days (SD 5·9) in the short treatment group versus 13·5 days (6·2) in the long treatment group, leading to an estimated difference of -4·0 days (95% CI -6·0 to -1·9; p=0·0002). Serious adverse events occurred in ten (22%) of 45 episodes in the short treatment group and nine (21%) of 43 in the long treatment group (risk ratio 1·06 [95% CI 0·46-2·47]). No deaths occurred. INTERPRETATION: Early discontinuation of intravenous antibiotics regardless of neutrophil recovery reduced unnecessary antibiotic exposure without indications of compromised safety. Although the study was not powered to detect differences in rare safety outcomes, it provides evidence for this approach in the management of children with cancer and high-risk febrile neutropenia. FUNDING: Danish Childhood Cancer Foundation, Danish Cancer Society, Innovation Fund Denmark.

BACKGROUND: Modulating the cGAS-STING pathway by bioactive nanodevices is a promising strategy for combating infection-associated inflammatory disorders. However, the development of pharmacological inhibitors for cGAS-STING signaling is currently hindered by lacking cell-specific targeting capability. This study aimed to develop a potent, drug-free nanodevice that specifically targets pulmonary macrophages to modulate the cGAS-STING pathway for ameliorating infection-associated detrimental lung inflammation. METHODS: Cigarette smoke extract-modified peptide gold nanoparticle hybrids (CSE-P12) were synthesized. Transcriptomic analysis, western blotting, autophagy reporter assays, and confocal microscopy were employed to assess the effects of CSE-P12 on gene expression, STING degradation, autophagic flux, and inflammation. TEM imaging and LC-MS/MS were utilized to elucidate the molecular mechanisms underlying CSE-P12-induced autophagy in macrophages. Finally, the HAdV4-induced pneumonia and CLP-induced sepsis models on wild-type and STING RESULTS: CSE-P12 nanodevices are extensively internalized by macrophages via energy-dependent cellular uptake. This large internalization triggers autophagic degradation of STING, thereby effectively inhibiting the cGAS-STING-mediated interferon responses and inflammation. In the HAdV4-induced viral pneumonia mouse model, intratracheally instilled CSE-P12 effectively targets pulmonary macrophages, suppresses STING activation, and significantly alleviates lung inflammation and injury. The depletion of the pulmonary macrophages abolishes these protective effects. The therapeutic potential of CSE-P12 is further validated in a CLP-induced polymicrobial sepsis mouse model, where it significantly prolongs mouse survival and decreases lung inflammation. CONCLUSIONS: CSE-P12 effectively targets pulmonary macrophages and exhibits potent anti-inflammatory activities in viral pneumonia and sepsis-induced acute lung injury by inducing autophagic flux to facilitate STING degradation. This work provides a new paradigm for designing targeted nanotherapeutics to modulate STING activation in inflammatory diseases.

Sepsis-associated encephalopathy (SAE) is a common and debilitating complication of sepsis, yet its cellular mechanisms and targeted therapies remain unclear. Microglia preserve neuroinflammatory homeostasis and neural circuit integrity through efferocytosis, but how this process is altered in SAE and regulated by immunometabolism is poorly defined. Here, we investigated the molecular basis of microglial efferocytosis impairment using LPS-stimulated BV2 cells and a cecal ligation and puncture (CLP) murine SAE model. We integrated RNA sequencing, HIF-1α and SLC7A11 gain- and loss-of-function approaches and in vitro functional assays. In vivo, HIF-1α was pharmacologically inhibited (KC7F2) or stabilized (DMOG) to evaluate its role in SAE. We assessed microglial efferocytosis and polarization, neuronal and synaptic integrity, cognition, survival, and brain metabolomics. LPS induced a pro-inflammatory microglial phenotype and reduced efferocytosis mediators (Tyro3, Mertk, Axl), impairing clearance of apoptotic neurons. HIF-1α upregulation interacted with SLC7A11 to suppress the TAM-Rac1-NCKAP1 axis, leading to efferocytic failure; knockdown of HIF-1α or SLC7A11 restored efferocytosis. In CLP mice, HIF-1α/SLC7A11 elevation coincided with TAM-Rac1-NCKAP1 suppression. These results reveal that impaired microglial efferocytosis is a key but overlooked feature in SAE. KC7F2 restored efferocytosis, shifted cytokines toward anti-inflammatory profiles, improved cognition and survival, and normalized metabolomic signatures, while DMOG produced opposite effects. This work uncovers a previously unknown HIF-1α-SLC7A11 pathway driving microglial dysfunction in SAE, offering fresh insight into disease mechanisms and pointing to HIF-1α as a promising therapeutic target.