Daily Sepsis Research Analysis
Three studies advance sepsis science across the translational spectrum: (1) a multi-omics human-mouse investigation reveals early serine-centered metabolic rewiring that differentiates uncomplicated infection from sepsis; (2) a PROSPERO-registered meta-analysis clarifies the diagnostic value and limits of complete blood count parameters in neonatal sepsis; and (3) a 20-year population-based analysis delineates species shifts, resistance patterns, and sex differences in Candida bloodstream infect
Summary
Three studies advance sepsis science across the translational spectrum: (1) a multi-omics human-mouse investigation reveals early serine-centered metabolic rewiring that differentiates uncomplicated infection from sepsis; (2) a PROSPERO-registered meta-analysis clarifies the diagnostic value and limits of complete blood count parameters in neonatal sepsis; and (3) a 20-year population-based analysis delineates species shifts, resistance patterns, and sex differences in Candida bloodstream infection outcomes.
Research Themes
- Early metabolic biomarkers and mitochondrial pathways in sepsis onset
- Diagnostic accuracy of CBC parameters in neonatal sepsis
- Long-term epidemiology and antifungal resistance in Candida bloodstream infection
Selected Articles
1. Multi-Omics and -Organ Insights into Energy Metabolic Adaptations in Early Sepsis Onset.
This translational study integrates human serum metabolomics/lipidomics with mouse single-nucleus RNA-seq to reveal early serine-centered energy metabolic adaptations that distinguish uncomplicated infection from sepsis. Mitochondrial gene modules (Cox4i1, Cox8a, Ndufa4) are down-regulated across tissues, with liver-specific serine-dependent shifts. Findings suggest feasible early biomarkers and mitochondrial-metabolic targets for risk stratification.
Impact: Bridging presymptomatic human biomarkers with mechanistic in vivo validation advances early sepsis detection and illuminates mitochondrial pathways. It identifies specific metabolites and gene modules with translational potential.
Clinical Implications: Supports development of early risk-stratification assays using serine-centered metabolite panels and suggests evaluating mitochondrial bioenergetic pathways as therapeutic targets, particularly hepatic serine metabolism.
Key Findings
- Untargeted serum metabolomics/lipidomics in 152 presymptomatic surgical patients identified serine and aminoadipic acid as discriminators between postoperative uncomplicated infection and sepsis.
- Single-nucleus RNA-seq in a mouse sepsis model showed tissue-independent down-regulation of serine and energy-related genes with key roles for mitochondrial genes Cox4i1, Cox8a, and Ndufa4.
- Liver-specific serine-dependent metabolic shifts were highlighted, linking systemic metabolite signatures to organ-level energy metabolism.
- Integrative multi-omics across species indicates early bioenergetic failure as a unifying feature preceding sepsis onset.
Methodological Strengths
- Cross-species, multi-omics design integrating human metabolomics/lipidomics with mouse single-nucleus RNA-seq.
- Organ- and pathway-level resolution identifying mitochondrial gene modules linked to systemic metabolites.
Limitations
- Moderate human sample size from a surgical cohort may limit generalizability.
- External validation cohorts and prospective diagnostic performance metrics are needed.
Future Directions: Validate metabolite panels in multicenter cohorts, define predictive thresholds, and test serine/mitochondrial pathway modulation in preclinical and early-phase interventional studies.
Systemic metabolic dysregulation in sepsis critically impacts patient survival. To better understand its onset, untargeted serum metabolomics and lipidomics are analyzed from 152 presymptomatic patients undergoing major elective surgery, and identified key metabolites, including serine and aminoadipic acid, that differentiate postoperative uncomplicated infection from sepsis. Using single-nucleus RNA sequencing data from an in vivo mouse model of sepsis, tissue-independent down-regulation and tissue-specific differences of serine and energy-related genes including key module roles for the mitochondria-linked genes, Cox4i1, Cox8a, and Ndufa4 are identified. Finally, serine-dependent metabolic shifts, especially in the liver, are revealed by using
2. Population-based longitudinal study over two decades of Candida and Candida-like species bloodstream infection reveals gender and species differences in mortality, recurrence and resistance.
In 2,586 Candida/Candida-like bloodstream infection episodes over 20 years in Queensland, species distributions shifted with overall low antifungal resistance. Thirty-day mortality remained 21%; C. parapsilosis complex was linked to lower mortality, while C. tropicalis trended higher. Recurrence (3.1%) was associated with uncommon species and endovascular sources, and females exhibited higher fluconazole resistance.
Impact: Large-scale, population-based surveillance with rigorous modeling provides actionable insights into species dynamics, resistance, and risk factors that can refine empirical therapy and follow-up strategies.
Clinical Implications: Supports species-aware empiric antifungal choices, closer monitoring for recurrence in patients with uncommon species or endovascular sources, and consideration of sex-specific resistance patterns.
Key Findings
- Across 2,586 Ca-BSI episodes, C. albicans and C. parapsilosis complex declined, while Nakaseomyces glabratus and Candida dubliniensis increased.
- Overall resistance remained low: fluconazole 3.2% and echinocandins 0.7%; fluconazole resistance decreased from 4.5% to 2.2% over time (P<0.01).
- Thirty-day mortality was 21% and unchanged; C. parapsilosis complex associated with reduced mortality (aHR 0.44), while C. tropicalis trended higher (aHR 1.35).
- Recurrence within one year was 3.1%, linked to uncommon species (aSHR 6.60) and endovascular source (aSHR 4.42); males had lower recurrence risk (aSHR 0.57).
- Females exhibited higher fluconazole resistance (4.1% vs 2.4%, P=0.02); resistance was higher in recurrent episodes.
Methodological Strengths
- Population-wide, 20-year surveillance with linkage to clinical, microbiological, and outcome databases.
- Appropriate time-to-event modeling (Cox and Fine-Gray) for mortality and recurrence.
Limitations
- Retrospective design with potential residual confounding and incomplete susceptibility testing (1836/2586 isolates tested).
- Generalizability may be limited outside Queensland or differing healthcare settings.
Future Directions: Enhance prospective, real-time antifungal resistance surveillance, include emerging species (e.g., Candida auris), and evaluate targeted interventions for high-risk recurrence groups.
BACKGROUND: The global burden of bloodstream infection (BSI) due to Candida, and species previously classed as Candida (Candida-like species) is substantial. Recent emergence of Candida auris, fluconazole-resistant Candida parapsilosis and echinocandin-resistant Nakaseomyces glabratus emphasise the importance of global and regional surveillance. METHODS: Blood cultures with growth of Candida/Candida-like species in Queensland, Australia (population ≈ 5 million) over a 20-year period (1 January 2000-31 December 2019) were retrospectively identified. Clinical, microbiological and outcome information was obtained from state-wide databases. Cox proportional and Fine-Gray subdistribution hazard models were used to construct hazard ratios for 30-day all-cause case fatality and 1-year recurrence, respectively. RESULTS: A total of 2586 episodes (2420 patients) of Candida/Candida-like bloodstream infection (Ca-BSI) were identified; 249 episodes (9.5%) were in children. Candida albicans and C. parapsilosis complex reduced in frequency, whilst N. glabratus and Candida dubliniensis increased during the study. Of 1836 isolates tested, fluconazole (3.2%) and echinocandin (0.7%) resistance rates were low, with a decrease in fluconazole resistance observed from the first half of the study period to the latter half (4.5% versus 2.2%, P<0.01). Overall, 30-day all-cause mortality (21%) was unchanged: C. parapsilosis complex (aHR 0.44, 95% CI 0.32-0.60) was associated with decreased mortality, while C. tropicalis (aHR 1.35, 95% CI 0.95-1.93) was associated with an increase. Only 3.1% episodes demonstrated recurrence of Ca-BSI within one year. Presence of uncommon Candida species (aSHR 6.60, 95% CI 2.99-14.56) and an endovascular source of infection (aSHR 4.42, 95% CI 1.87-10.46) were associated with recurrence, while male gender (aSHR 0.57, 95% CI 0.35-0.92) was protective. Resistance to fluconazole (3.2% vs 3.5%, P=0.58) and echinocandins (0.6% vs 2.0%, P=0.05) was higher in recurrent Ca-BSI episodes. Females had a higher rate of fluconazole resistance (4.1% versus 2.4%, P=0.02). CONCLUSIONS: Our study highlights important shifts in causative species and resistance patterns of Ca-BSI which impacts clinical management. Antifungal resistance rates were low overall. The identification of new modifiable and non-modifiable risk factors for recurrence and mortality provides opportunities to examine new strategies to improve patient outcomes.
3. Role of complete blood count in the diagnosis of culture-proven neonatal sepsis: a systematic review and meta-analysis.
This PROSPERO-registered systematic review/meta-analysis found that functional CBC indices, especially ITR (>0.20), offer moderate diagnostic accuracy (sensitivity 66.3%, specificity 85.4%) for culture-proven neonatal sepsis. Mean neutrophil volume is promising, but heterogeneity limits generalization; CBC should augment, not replace, comprehensive sepsis evaluation.
Impact: Clarifies the real-world diagnostic contribution and limits of ubiquitous CBC testing in neonatal sepsis, guiding algorithms and resource-conscious care.
Clinical Implications: Use ITR thresholds (e.g., >0.20) and potentially MNV as adjuncts within sepsis bundles, while avoiding overreliance on CBC alone; standardize cut-offs and sampling timing in protocols.
Key Findings
- ITR >0.20 achieved pooled sensitivity 66.3% and specificity 85.4% for culture-proven neonatal sepsis.
- Mean neutrophil volume showed promising diagnostic utility but with substantial inter-study heterogeneity.
- CBC is rapid and low-volume, suitable as an adjunct rather than a stand-alone diagnostic tool in neonates.
Methodological Strengths
- PROSPERO-registered protocol and comprehensive multi-database search.
- Bias assessment with modified QUADAS-2 and pooled accuracy estimates across CBC parameters.
Limitations
- Substantial heterogeneity across studies, including varying definitions, thresholds, and timing of sampling.
- Potential publication bias and limited standardization of emerging parameters like MNV.
Future Directions: Prospective, standardized diagnostic accuracy studies harmonizing CBC thresholds/timing and integrating CBC with biomarkers (e.g., CRP, PCT) and clinical scores.
OBJECTIVE: Neonatal sepsis is a significant cause of morbidity and mortality, particularly in preterm infants. Despite its routine use in adults, the diagnostic utility of complete blood count (CBC) in neonatal sepsis remains debated. This systematic review and meta-analysis aimed to evaluate the diagnostic accuracy of CBC parameters for neonatal sepsis. METHODS: This review was registered at PROSPERO (CRD42023476510). MEDLINE, Embase, CINAHL and the Cochrane Library were searched from database inception to 28 October 2024. Observational studies of neonates with sepsis, published in English, were included. Pooled diagnostic accuracy metrics were calculated for CBC parameters, including the white cell count (WCC), neutrophil count and immature-to-total neutrophil ratio (ITR). Bias was assessed using a modified QUADAS-2 tool. RESULTS: Functional CBC parameters like ITR and mean neutrophil volume (MNV) showed moderate diagnostic accuracy. Pooled analysis revealed that an ITR >0.20 had 66.3% sensitivity and 85.4% specificity for neonatal sepsis. MNV also showed promising diagnostic utility, but substantial heterogeneity across studies (I CONCLUSIONS: The CBC is a rapid, cost-effective test requiring minimal blood volume, making it a practical adjunct in neonatal diagnostics. Functional parameters like ITR and MNV show the potential to complement existing approaches but are insufficient as stand-alone diagnostic tools. Further research is needed to validate their clinical utility and address heterogeneity in study designs.