Daily Sepsis Research Analysis
Analyzed 44 papers and selected 3 impactful papers.
Summary
Three high-impact studies advanced sepsis science and care: an RCT showed procalcitonin-guided management safely shortens antibiotics in neonatal late-onset sepsis; mechanistic work identified soluble uric acid as a suppressor of neutrophil host defense with partial reversal by urate-lowering; and pediatric SA-AKI subphenotypes were externally validated with distinct biomarker signatures and heterogeneous treatment effects.
Research Themes
- Antimicrobial stewardship in neonatal sepsis
- Immunometabolism and neutrophil dysfunction in sepsis
- Precision subphenotyping for sepsis-associated acute kidney injury
Selected Articles
1. Procalcitonin-guided decision and antibiotic treatment duration in late onset sepsis of newborns: multicentre, randomised controlled trial (ProABIS).
In a 33-center randomized trial of 504 neonates with suspected/proven late-onset sepsis, procalcitonin-guided recommendations shortened antibiotic duration (median 8 vs 10 days; P<0.001) without increasing 28-day mortality or recurrence. This supports PCT-based stewardship strategies in neonatal sepsis pathways.
Impact: This is a multicenter RCT demonstrating a safe reduction of antibiotic exposure in a high-risk neonatal population, directly informing stewardship and guideline implementation.
Clinical Implications: Integrate PCT monitoring (threshold ≤0.5 µg/L, assessed every 48 hours) into neonatal late-onset sepsis protocols to safely reduce antibiotic days, while ensuring cultures are obtained and excluding meningitis/shock/deep infections.
Key Findings
- Antibiotic duration was reduced by a median of 2 days with PCT guidance (8 vs 10 days; P<0.001).
- 28-day mortality was similar: 2.4% (PCT) vs 3.9% (usual care); absolute difference −1.5% (95% CI −5.0 to 1.8).
- Recurrence rates were comparable: 2.8% (PCT) vs 3.9% (usual care).
- Operational protocol used a non-binding stop recommendation when PCT ≤0.5 µg/L, measured every 2 days.
Methodological Strengths
- Multicenter randomized design across 33 neonatal units with intention-to-treat analysis.
- Prospectively registered (NCT03730636) with clear protocols and clinically relevant endpoints.
Limitations
- Open-label design with non-binding recommendations may introduce clinician-driven variability.
- Exclusion of meningitis, septic shock, and deep-seated infections limits generalizability to all neonatal sepsis cases.
Future Directions: Evaluate implementation at scale, cost-effectiveness, and performance in higher-risk subgroups; refine stopping thresholds and integration with other biomarkers.
OBJECTIVE: To assess whether procalcitonin-guided decision making can safely reduce the duration of antibiotic treatment in neonatal late onset sepsis. DESIGN: Prospective multicentre, randomised open label trial. SETTING: 33 level 3 and level 2B neonatology departments in France. PARTICIPANTS: Newborn babies born after 24 weeks' gestation, of postconceptional age 24-45 weeks and after 4 days of life, weighing more than 700 g, with suspected or proven late onset sepsis, requiring antibiotics for more than 48 hours, and without meningitis, septic shock, and deep-seated infection. INTERVENTIONS: Participants were randomly assigned to procalcitonin-guided or usual care antibiotic treatment. In the procalcitonin-guided group, procalcitonin concentration was measured at randomisation and then every two days. A non-binding recommendation to discontinue antibiotics was given if the procalcitonin concentration was 0.5 µg/L or lower. In the usual care group, treatment was provided according to local protocols. MAIN OUTCOME MEASURES: The primary outcome was the duration of antibiotic treatment (under the superiority hypothesis). The key secondary outcome was non-inferiority for mortality (margin 3%) at day 28 after randomisation. RESULTS: Between February 2019 and February 2023, 248 newborns were randomised to the procalcitonin-guided group and 256 to the usual care group. In the intention-to-treat analysis, the median duration of antibiotic treatment was eight days (interquartile range (IQR) 5.0-12.0) in the procalcitonin-guided group versus 10 days (8.0-13.0) in the usual care group (absolute difference between groups -2.0 (IQR -3.8 to -1.0), P<0.001). At day 28, the proportion of death was six of 248 newborns (2.4%) in the procalcitonin-guided group versus 10 of 256 (3.9%) in the usual care group (absolute difference between groups -1.5% (95% confidence interval (CI) -5.0 to 1.8). The proportion of recurrence was seven of 248 (2.8%) newborns in the procalcitonin-guided group versus 10 (3.9%) of 256 in the usual care group (absolute difference between groups -1.1% (95% CI -4.6 to 2.3). CONCLUSION: In this study population, the use of procalcitonin significantly reduced the duration of antibiotic treatment in neonatal late onset sepsis, without increasing mortality or serious adverse events. TRIAL REGISTRATION: NCT03730636.
2. Soluble uric acid suppresses neutrophil-mediated host defense in sepsis.
Across murine endotoxemia/bacterial sepsis models and human neutrophils, soluble uric acid amplified hyperinflammation but impaired phagocytosis and bacterial killing by reducing NOX2-dependent ROS; urate lowering (febuxostat) partially reversed defects. Hyperuricemia emerges as an immunometabolic driver of sepsis-related immune dysfunction.
Impact: This mechanistic study links hyperuricemia to impaired neutrophil host defense in sepsis and shows partial reversibility with urate-lowering therapy, opening a tractable translational avenue.
Clinical Implications: Consider monitoring and addressing hyperuricemia in septic or high-risk (e.g., CKD) patients as a potential strategy to improve innate immune function; interventional trials of xanthine oxidase inhibition in sepsis are warranted before routine adoption.
Key Findings
- Hyperuricemia exacerbated inflammatory responses in murine endotoxemia and bacterial sepsis while impairing host defense.
- Soluble uric acid reduced neutrophil phagocytosis and NOX2 expression, diminishing ROS and bacterial killing; NET formation was unaffected.
- Lowering uric acid (e.g., febuxostat) partially restored neutrophil functions; depleting UA in CKD serum improved human neutrophil activity.
Methodological Strengths
- Integrated in vivo murine models (endotoxemia and sepsis) with human neutrophil/serum experiments for translational relevance.
- Mechanistic dissection implicating NOX2-dependent ROS with partial reversal by pharmacologic urate lowering.
Limitations
- No clinical trials assessing urate-lowering therapy in sepsis; translational gap remains.
- Partial reversibility suggests additional pathways; potential confounding in CKD-related immune dysfunction.
Future Directions: Prospective trials testing xanthine oxidase inhibitors or urate-lowering strategies in sepsis, with biomarker-guided selection (urate, NOX2/ROS metrics) and infection-specific outcomes.
Neutrophils are essential for host defense and inflammation, yet their dysfunction is a hallmark of acquired immunodeficiency in kidney disease, contributing to increased susceptibility to infections such as peritonitis, sepsis, and pneumonia. We speculated that impaired renal clearance of the metabolite soluble uric acid (sUA) accounts for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-14 mg/dL) related or unrelated to kidney disease significantly exacerbates the inflammatory immune response in mice with endotoxemia and bacterial sepsis. Despite promoting hyperinflammation, HU simultaneously impairs host defense, an effect that is partially reversible by lowering UA levels with febuxostat. We validated these findings in vitro using neutrophils or serum from healthy individuals or hyperuricemic patients with chronic kidney disease. Depleting UA partially restores neutrophil function. Mechanistically, sUA promotes neutrophil activation and degranulation but impairs phagocytosis, leading to reduced NOX2 expression independent of intracellular MPO levels. This results in diminished ROS production and defective bacterial clearance in human neutrophils. In contrast, sUA has no impact on neutrophil extracellular trap formation following exposure to LPS or E.coli. Together, our findings identify HU as an immunometabolic regulator that amplifies hyperinflammation, while simultaneously impairing effective host defense, suggesting that targeting UA may help to overcome acquired immunodeficiency in kidney disease.
3. External Validation, Molecular Signatures, and Therapeutic Relevance of Pediatric Sepsis-Associated Acute Kidney Injury Subphenotypes.
In an external validation across 10 PICUs (n=871), two pediatric SA-AKI subphenotypes showed distinct severity, outcomes, and biomarker profiles; the high-risk pSAKI-2 had markedly worse outcomes. Heterogeneous treatment effects were observed: corticosteroids were associated with harm in pSAKI-1, and vasopressin effects varied by subphenotype.
Impact: This study advances precision medicine in pediatric sepsis by validating clinically-derivable subphenotypes with molecular signatures and demonstrating heterogeneity of treatment effects to inform bedside enrichment and trial design.
Clinical Implications: Use early clinical data to classify pediatric SA-AKI into subphenotypes to guide risk stratification and therapeutic choices; exercise caution with corticosteroids in pSAKI-1 and consider phenotype-specific responses when using vasopressin.
Key Findings
- Two reproducible pediatric SA-AKI subphenotypes were externally validated (pSAKI-1: 76%; pSAKI-2: 24%).
- pSAKI-2 had higher severity and worse outcomes: day 7 severe AKI (aOR 3.2), mortality (aOR 2.7), and fewer PICU-/vasoactive-free days.
- Biomarkers in pSAKI-2 indicated greater inflammation, endothelial dysfunction, and hyperreninemia.
- Corticosteroids were associated with harm in pSAKI-1 (higher day 7 severe AKI, fewer PICU-free days, higher mortality); vasopressin effects varied by subphenotype in IPTW analysis.
Methodological Strengths
- Multicenter prospective observational cohort with large sample and long enrollment window; rigorous external validation.
- Advanced causal methods (PSM, IPTW) and integration of biomarker profiling with clinical subphenotypes.
Limitations
- Observational design with potential residual confounding and treatment selection bias.
- HTE signals require prospective confirmation; generalizability beyond US PICUs or to adults is uncertain.
Future Directions: Prospective, phenotype-enriched interventional trials (e.g., corticosteroids, vasopressin) and development of rapid bedside tools to assign subphenotypes.
OBJECTIVE: Sepsis-associated acute kidney injury (SAKI) is a heterogeneous condition that lacks disease-modifying treatments, and precision medicine approaches are needed. We previously derived two reproducible pediatric SAKI subphenotypes (pSAKI-1 and pSAKI-2) from readily available clinical data. We aimed to externally validate the prognostic relevance of these subphenotypes, evaluate their molecular signatures, and assess for heterogeneity of treatment effect (HTE) across subphenotypes with sepsis therapies. DESIGN: Secondary analysis of an ongoing multicenter, prospective, observational study of children. SETTING: Ten PICUs in the United States from January 2002 to February 2025. PATIENTS: Patients 1 week to 18 years old with early (day 1-2) SAKI. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 871 patients, 665 (76%) were assigned pSAKI-1 and 206 (24%) to pSAKI-2. On day 1-2, the pSAKI-2 cohort had greater severity of illness, including higher acute kidney injury stage and vasoactive burden, lower platelet counts, and higher lactate values and International Normalized Ratios. These pSAKI-2 patients also had uniformly worse outcomes, including independently higher odds of day 7 severe acute kidney injury (adjusted odds ratio [aOR] 3.2; 95% CI, 2.1-4.7; p < 0.001), death (aOR 2.7; 95% CI, 1.6-4.4; p < 0.001), and fewer PICU-free and vasoactive-free days (p < 0.001). The biomarker signature of pSAKI-2 was characterized by greater inflammation, endothelial dysfunction, and hyperreninemia. On propensity score matched (PSM) analysis, pSAKI-1 patients who received corticosteroids had more day 7 severe acute kidney injury (28% vs. 19%, p = 0.023), 2 fewer PICU-free days (p = 0.04) and greater mortality (10% vs. 3.7%, p = 0.008); no differences were seen in pSAKI-2 patients. Although no HTE was identified on PSM analysis for vasopressin, inverse probability treatment weighting analysis demonstrated a significant interaction between subphenotype-, vasopressin- and vasoactive-free days (p = 0.003). CONCLUSIONS: We externally validated the prognostic relevance of two pSAKI subphenotypes derived from readily available data. These subphenotypes have unique biomarker signatures and differential responses to treatment, representing a potential mechanism for bedside enrichment.