Daily Sepsis Research Analysis
Three high-impact sepsis studies stood out: a preclinical mechanistic study identifies macrophage BTK→Rap1→NF-κB signaling as a driver of sepsis-induced thrombocytopenia and shows rescue by a BTK inhibitor; a systematic review/meta-analysis supports omitting antibiotic prophylaxis for transperineal prostate biopsy without increasing sepsis; and a preclinical study demonstrates that TBC1D15 restores mitophagy and mitigates sepsis-induced acute lung injury.
Summary
Three high-impact sepsis studies stood out: a preclinical mechanistic study identifies macrophage BTK→Rap1→NF-κB signaling as a driver of sepsis-induced thrombocytopenia and shows rescue by a BTK inhibitor; a systematic review/meta-analysis supports omitting antibiotic prophylaxis for transperineal prostate biopsy without increasing sepsis; and a preclinical study demonstrates that TBC1D15 restores mitophagy and mitigates sepsis-induced acute lung injury.
Research Themes
- Immunothrombosis and hematopoiesis in sepsis
- Antibiotic stewardship and sepsis prevention in procedures
- Mitochondrial quality control and organ injury in sepsis
Selected Articles
1. Impaired megakaryopoiesis due to aberrant macrophage polarization via BTK/Rap1/NF-κB pathway in sepsis-induced thrombocytopenia.
This preclinical study connects macrophage BTK activation to impaired megakaryopoiesis in sepsis-induced thrombocytopenia. Pharmacologic BTK inhibition (BGB-3111) restored megakaryocyte and platelet production in mice via a Rap1/NF-κB–dependent effect on macrophage polarization.
Impact: Identifies a tractable immune–hematopoietic mechanism for sepsis-induced thrombocytopenia and repurposes an approved BTK inhibitor class as a potential therapy. Offers mechanistic biomarkers (p-BTK, macrophage polarization) for translational studies.
Clinical Implications: Supports testing BTK inhibitors (e.g., zanubrutinib) in septic patients with severe thrombocytopenia, with careful safety monitoring given infection risks. Platelet count recovery could be mediated by modulating macrophage polarization rather than direct thrombopoiesis.
Key Findings
- SIT patients and septic mice exhibited increased pro-inflammatory macrophages and elevated macrophage p-BTK, correlating inversely with platelet counts.
- BTK inhibitor BGB-3111 increased megakaryocyte and platelet production in SIT mice.
- Macrophage depletion and coculture experiments confirmed macrophages as key mediators of platelet recovery upon BTK inhibition.
- Single-cell RNA-seq implicated Rap1 signaling linking macrophages to megakaryopoiesis under BTK influence.
- BTK inhibition reduced pro-inflammatory macrophage polarization via Rap1/NF-κB.
Methodological Strengths
- Integrated in vivo SIT mouse model, macrophage depletion, pharmacologic inhibition, and coculture validation
- Single-cell RNA sequencing delineating cell–cell signaling pathways
Limitations
- Preclinical models; no human interventional data
- Potential off-target and infection risks of BTK inhibitors in sepsis not assessed
Future Directions: Conduct early-phase clinical trials of BTK inhibition in sepsis-induced thrombocytopenia, validate Rap1/NF-κB signaling biomarkers, and define patient selection criteria (e.g., high p-BTK macrophage signature).
Sepsis-induced thrombocytopenia (SIT) is a widely accepted predictor of poor prognosis during sepsis, while the mechanism of SIT remains elusive. In this study, we revealed that SIT patients and septic mice exhibited higher levels of pro-inflammatory macrophages and phosphorylated Bruton's tyrosine kinase (p-BTK) expression in macrophages, which were closely correlated with platelet counts. Treatment with the BTK inhibitor BGB-3111 in SIT mice resulted in enhanced production of megakaryocytes and platelets. Depletion of macrophages in SIT mice and coculture experiments further confirmed the critical role of macrophages in the improvement of platelet count induced by BGB-3111. By performing single-cell RNA sequencing on bone marrow-derived cells from SIT mice, we not only confirmed the connection between macrophages and megakaryocytes influenced by BTK but also identified a potential mediation through the Rap1 signaling pathway in macrophages. Subsequent experiments in macrophages demonstrated that inhibition of BTK signaling impeded the pro-inflammatory polarization of macrophages by targeting the Rap1/NF-κB signaling pathway. In conclusion, our study highlights the crucial role of macrophages in SIT, and inhibiting phosphorylation of BTK in macrophages may alleviate SIT through the Rap1/NF-κB signaling pathway.
2. Infectious complications following transperineal prostate biopsy with or without periprocedural antibiotic prophylaxis-a systematic review including meta-analysis of all comparative studies.
Across 23 comparative studies (including two RCTs; n≈12,324), omitting periprocedural antibiotic prophylaxis for transperineal prostate biopsy did not increase genitourinary infections, fever, sepsis (0.16% vs 0.13%), or readmissions. Findings support antibiotic stewardship without compromising patient safety.
Impact: Directly informs practice by showing no infection/sepsis reduction from prophylaxis in TPB, enabling de-implementation of routine antibiotics and reducing resistance pressure.
Clinical Implications: Routine antibiotic prophylaxis for transperineal prostate biopsy can be safely omitted in most patients, aligning with stewardship goals; protocols should still consider high-risk individuals based on local epidemiology.
Key Findings
- No significant differences in GUI, fever, sepsis, or readmission between TPB with vs without prophylaxis (all p>0.25).
- Pooled sepsis incidence was very low and similar (0.16% with PAP vs 0.13% without).
- Subgroup and sensitivity analyses confirmed robustness; 30-day mortality was not observed.
Methodological Strengths
- Comprehensive multi-database and grey literature search with GRADE assessment
- Inclusion of randomized and non-randomized comparative studies with large aggregate sample
Limitations
- Heterogeneous study designs and incomplete endpoint reporting across studies
- Very low event rates limit precision for rare outcomes
Future Directions: Define criteria for selective prophylaxis in specific high-risk subgroups and evaluate cost-effectiveness and resistance impact of de-implementation.
BACKGROUND: Despite the relatively low infection rate following transperineal prostate biopsy (TPB), it remains unresolved whether periprocedural antibiotic prophylaxis (PAP) can be omitted. Our aim was to compare infectious complications (genitourinary infections/GUI, fever, sepsis, readmission rate, 30-day-mortality) following TPB, considering all studies of varying levels of evidence that enable a direct comparison between patients with and without PAP. METHODS: We performed a comprehensive search in PubMed/Medline, Embase, Web of Science, and Cochrane databases, as well as grey literature sources, to identify reports published until January 2024. All studies comparing the incidence of infectious endpoints following TPB with vs. without PAP were included in the analyses. The GRADE approach was employed to assess the certainty of evidence for each comparison. RESULTS: Twenty-three studies met the inclusion criteria involving 6520 and 5804 patients who underwent TPB with vs. without PAP, respectively. Two of the 23 studies were randomized-controlled trials, not all studies investigated all endpoints. Pooled incidences between patients with vs. without PAP for the endpoints GUI (0.50% vs. 0.37%), fever (0.44% vs. 0.26%), sepsis (0.16% vs. 0.13%), and readmission rate (0.35% vs. 0.29%) showed no significant differences (all p > 0.250). The corresponding odds ratios (including 95% confidence interval) also revealed no statistically significant differences: 1.37 (0.74-2.54) [GUI], 0.87 (0.28-2.66) [fever], 1.30 (0.46-3.67) [sepsis], and 1.45 (0.70-3.03) [readmission rate]. No study reported events regarding 30-day-mortality. In subgroup analyses and sensitivity analyses, TPB without PAP showed no significantly higher complication rates regarding all analyzed endpoints. CONCLUSIONS: Infectious complications after TPB occur very rarely and cannot be further reduced by PAP. Considering the results of this systematic review and adhering to the principles of effective antibiotic stewardship, omitting PAP in the context of TPB is advisable.
3. The role of TBC1D15 in sepsis-induced acute lung injury: Regulation of mitochondrial homeostasis and mitophagy.
TBC1D15 expression is reduced in sepsis and its overexpression restores mitophagy, shortens pathological mitochondria–lysosome contact, and attenuates lung injury and inflammation in SI-ALI models. The protective effects are mitophagy-dependent, as pharmacologic inhibition abrogates benefit.
Impact: Reveals a mitochondria-lysosome contact/mitophagy axis as a modifiable pathway in septic lung injury and nominates TBC1D15 as a therapeutic target.
Clinical Implications: Suggests potential for mitophagy-enhancing strategies or TBC1D15-targeted approaches in sepsis-induced lung injury; clinical translation will require safety and efficacy studies.
Key Findings
- TBC1D15 levels were decreased in sepsis patient blood, monocytes, SI-ALI mouse lungs, and MLE-12 cells.
- TBC1D15 overexpression reduced lung injury and inflammation while promoting mitophagy and mitochondrial function.
- Mitophagy inhibition with Bafilomycin A1 abrogated TBC1D15’s protective effects.
- TBC1D15 knockdown prolonged mitochondria–lysosome contact, worsening mitochondrial dysfunction and oxidative stress.
Methodological Strengths
- Convergent evidence across patient samples, mouse models, and lung epithelial cells
- Genetic gain-/loss-of-function with pharmacologic validation of mitophagy dependence
Limitations
- Preclinical study without human interventional data
- Overexpression/viral delivery may not directly translate to clinical modalities
Future Directions: Elucidate upstream regulators of TBC1D15 in sepsis, screen small molecules to modulate TBC1D15/mitophagy, and test efficacy in large-animal models prior to clinical trials.
Mitochondrial quality control is crucial in sepsis-induced acute lung injury (SI-ALI). Our study investigates how the intracellular protein TBC1D15 regulates mitochondrial quality to improve SI-ALI. We found TBC1D15 levels significantly decreased in the whole blood of sepsis patients, monocytes, lung tissue from SI-ALI mice, and the MLE-12 cellular model (mouse lung epithelial cells). Overexpression of TBC1D15 using adeno-associated viral and lentiviral vectors alleviated lung injury and inflammation in both mouse models and MLE-12 cells, while silencing TBC1D15 exacerbated inflammatory responses. Mechanistically, TBC1D15 overexpression dissociated mitochondria-lysosome contact duration, promoted mitophagy, and restored mitochondrial function. The protective effects of TBC1D15 were reversed by the mitophagy inhibitor Bafilomycin A1. Additionally, TBC1D15 knockdown prolonged mitochondria-lysosome contact time, resulting in worsened mitochondrial dysfunction and increased oxidative stress. Our findings indicate that SI-ALI is characterized by prolonged mitochondria-lysosome contact and impaired mitophagy. Thus, TBC1D15 overexpression presents a promising therapeutic strategy to mitigate mitochondrial dysfunction and reduce lung injury in septic conditions, suggesting potential clinical applications for SI-ALI treatment.