Daily Sepsis Research Analysis
Precision medicine and diagnostics led today’s sepsis research. A secondary analysis of the ADRENAL RCT found no overall endotype-specific benefit of hydrocortisone in septic shock, but a harm signal in pulmonary sepsis with an adaptive-prevalent immune endotype. A nationwide cohort linked early-onset neonatal sepsis to increased autism risk, and a microchip assay showed high accuracy for detecting β-lactam resistance genes directly from positive blood cultures.
Summary
Precision medicine and diagnostics led today’s sepsis research. A secondary analysis of the ADRENAL RCT found no overall endotype-specific benefit of hydrocortisone in septic shock, but a harm signal in pulmonary sepsis with an adaptive-prevalent immune endotype. A nationwide cohort linked early-onset neonatal sepsis to increased autism risk, and a microchip assay showed high accuracy for detecting β-lactam resistance genes directly from positive blood cultures.
Research Themes
- Precision therapeutics and endotyping in septic shock
- Long-term neurodevelopmental outcomes after neonatal sepsis
- Rapid molecular diagnostics for antimicrobial resistance in bloodstream infection
Selected Articles
1. A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial.
Among 540 septic shock patients, gene expression-defined endotypes (IA-P vs IN-P) were roughly equal, and hydrocortisone showed no heterogeneity of treatment effect on 28-day mortality overall. In pulmonary sepsis, IA-P patients receiving hydrocortisone had higher mortality, suggesting potential harm in this subgroup.
Impact: This RCT-based endotyping analysis advances precision medicine in septic shock and flags a plausible harm signal for hydrocortisone in a biologically defined pulmonary sepsis subgroup.
Clinical Implications: Routine steroid use in septic shock may warrant re-evaluation in pulmonary sepsis with an adaptive-prevalent endotype; prospective, real-time endotyping to guide steroids should be tested before practice change.
Key Findings
- 540 septic shock patients were classified into IA-P (49.4%) and IN-P (50.6%) immune endotypes using predefined gene expression signatures.
- No overall heterogeneity of hydrocortisone effect on 28-day mortality between IA-P and IN-P (Bayesian OR ~1.4 with wide credible intervals).
- In pulmonary sepsis (n=232), IA-P patients treated with hydrocortisone had increased mortality (OR 5.55, 95% CrI 1.81–21.2).
- Severe shock subgroup analyses did not show endotype-specific differences in hydrocortisone effect.
Methodological Strengths
- Predefined gene expression signatures to classify immune endotypes
- Bayesian analysis and use of randomized trial cohort (ADRENAL) enhancing internal validity
Limitations
- Secondary analysis with potential for residual confounding and multiple comparisons
- Harm signal in pulmonary sepsis IA-P subgroup is based on subgroup analysis with limited sample and wide credible intervals
Future Directions: Prospective trials testing steroid strategies stratified by real-time endotyping, and mechanistic studies to elucidate why IA-P pulmonary sepsis might be harmed by corticosteroids.
BACKGROUND: Small observational studies suggest the effect of corticosteroids in patients with vasodilatory shock vary depending on endotypes determined by gene expression. We sought to replicate these findings in a larger cohort from a randomised clinical trial. METHODS: In a cross-sectional substudy of the Adjunctive Glucocorticoid Therapy In Septic Shock (ADRENAL) trial, patients were classified as one of two immune endotypes using predefined gene expression signatures: immune adaptive-prevalent (IA-P) or immune innate-prevalent (IN-P). We compared the outcomes of the two endotypes using a Bayesian analysis. The primary outcome was Day-28 mortality.
2. Early-Onset Neonatal Infection and Attention Deficit Hyperactivity and Autism Spectrum Disorder: A Nationwide Cohort Study.
Among 981,869 children, early-onset sepsis was associated with increased risk of ASD (adjusted HR 1.43) and a modest increase for ADHD (HR 1.28) that attenuated in sibling-matched analyses (HR 1.12). Culture-confirmed cases were few, but findings suggest a neurodevelopmental signal primarily for ASD.
Impact: This very large, methodologically rigorous cohort with sibling controls links early neonatal sepsis to later autism risk, informing surveillance strategies and hypotheses on brain–immune interactions.
Clinical Implications: Children with early-onset neonatal sepsis may benefit from targeted developmental surveillance and early intervention pathways; prevention of neonatal invasive infections remains critical.
Key Findings
- Early-onset sepsis was associated with increased ASD risk (adjusted HR 1.43, 95% CI 1.30–1.58).
- Association with ADHD was weaker (HR 1.28, 95% CI 1.17–1.39) and attenuated in sibling-matched analyses (HR 1.12, 95% CI 0.93–1.34).
- Culture-positive sepsis and meningitis cases were few (sepsis n=257; meningitis n=32), with meningitis showing point estimates suggestive of increased risk but wide CIs.
Methodological Strengths
- Nationwide registry cohort with nearly one million participants and long follow-up
- Sibling-matched analyses to control for shared familial confounding
Limitations
- Observational design with potential residual confounding and misclassification from diagnosis codes
- Low number of culture-confirmed infections limits pathogen-specific inference
Future Directions: Replicate in other populations, integrate granular perinatal and infection severity data, and investigate mechanistic pathways linking neonatal inflammation to neurodevelopment.
BACKGROUND: Early-onset neonatal infections are among the most common neonatal diseases. However, the long-term outcomes of the infections are not well understood. OBJECTIVE: To study the association between early-onset neonatal infection and attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). METHODS: A nationwide register-based cohort study was conducted, including near-term and term children born between 1997 and 2013 with follow-up until 2021. An early-onset infection was defined as an invasive bacterial infection occurring within the first week of life, including both physician-assigned diagnoses and positive bacterial cultures. ADHD and ASD were defined by diagnoses or prescriptions of relevant medication. Associations between sepsis and the neurodevelopmental disorders were investigated using multivariable Cox regression to estimate adjusted hazard ratios (HR), whereas associations with meningitis were examined using person-time incidence rate ratios (IRR). Sibling-matched analyses were also conducted for associations with sepsis.
3. Detection of β-lactam resistance genes in Gram-negative bacteria from positive blood cultures using a microchip-based molecular assay.
A microchip-based assay detected β-lactam resistance genes directly from positive blood cultures with high accuracy, correctly identifying 99.5% of target genes in simulated samples and showing broader gene coverage than BCID2. Clinical sample testing supports potential routine use, pending prospective validation.
Impact: Rapid genotypic resistance profiling directly from blood cultures could enable earlier targeted therapy and stewardship, particularly for Gram-negative sepsis.
Clinical Implications: Laboratories could complement or bridge phenotypic AST with rapid gene detection to guide early de-escalation/escalation; confirmatory phenotypic testing remains essential.
Key Findings
- The microchip assay correctly identified 203/204 (99.5%) β-lactam resistance genes in simulated GN positive blood culture samples.
- Demonstrated broader β-lactam resistance gene coverage compared with BCID2.
- Feasibility supported by testing in both simulated (n=146) and clinical (n=106) samples.
Methodological Strengths
- Direct-from-positive blood culture testing reduces time to genotypic results
- Head-to-head comparison indicating broader gene coverage than an established panel (BCID2)
Limitations
- Use of simulated samples may overestimate performance relative to real-world clinical diversity
- Clinical sample size was modest; genotype may not always predict phenotype
Future Directions: Prospective multicenter studies to quantify impact on time to effective therapy, clinical outcomes, and cost-effectiveness, and integration with stewardship workflows.
BACKGROUND: Accurate detection of β-lactam resistance genes in bloodstream infections is critical for guiding antimicrobial therapy. This study evaluates the Alifax Gram-negative resistance (GNR) microchip assay for detecting β-lactam resistance genes directly from positive blood cultures (PBCs) for Gram-negative (GN) bacteria, including Enterobacterales, METHODS: Simulated (n=146) and clinical (n=106) GN-PBC samples were tested for RESULTS: The GNR microchip assay correctly identified 203 (99.5%) of 204 β-lactam resistance genes in simulated samples. One sample tested false negative for a CONCLUSION: The GNR microchip assay demonstrated high concordance and broader β-lactam resistance gene coverage compared to BCID2, supporting its potential role in routine diagnostics. Further validation in larger, prospective studies is warranted.