Daily Sepsis Research Analysis
A definitive phase 3 RCT (TESTS) found no mortality benefit of thymosin α1 in adults with sepsis, underscoring the need for biomarker-guided immunotherapy. A prospective ICU study showed that bedside ultrasonographic optic nerve sheath diameter (ONSD) robustly predicted sepsis-associated encephalopathy. Mechanistic work continues to evolve, but immediate clinical gains are seen in diagnostic stratification and the repudiation of ineffective immunostimulants.
Summary
A definitive phase 3 RCT (TESTS) found no mortality benefit of thymosin α1 in adults with sepsis, underscoring the need for biomarker-guided immunotherapy. A prospective ICU study showed that bedside ultrasonographic optic nerve sheath diameter (ONSD) robustly predicted sepsis-associated encephalopathy. Mechanistic work continues to evolve, but immediate clinical gains are seen in diagnostic stratification and the repudiation of ineffective immunostimulants.
Research Themes
- Immunomodulation in sepsis: efficacy signals and trial design
- Noninvasive neurocritical monitoring for sepsis-associated encephalopathy
- Diagnostic biomarker combinations in neonatal sepsis
Selected Articles
1. The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial.
In a multicentre, double-blind phase 3 RCT of 1106 adults with sepsis, thymosin α1 did not reduce 28-day all-cause mortality versus placebo (HR 0.99). No secondary or safety endpoints differed; age and diabetes showed interaction signals, which are hypothesis-generating.
Impact: This definitive trial refutes a mortality benefit of thymosin α1 in sepsis, guiding de-implementation and informing future biomarker-driven immunotherapy trials.
Clinical Implications: Routine use of thymosin α1 for adult sepsis should be avoided. If considered, it should be restricted to clinical trials with immunophenotyping and pre-specified enrichment strategies.
Key Findings
- 28-day all-cause mortality was 23.4% with thymosin α1 vs 24.1% with placebo (HR 0.99, 95% CI 0.77–1.27; P=0.93).
- No significant differences in secondary or safety outcomes between groups.
- Pre-specified subgroup interactions: age (<60 years HR 1.67 vs ≥60 years HR 0.81; interaction P=0.01) and diabetes (diabetes HR 0.58 vs no diabetes HR 1.16; interaction P=0.04).
- Intervention: subcutaneous thymosin α1 every 12 hours for 7 days.
Methodological Strengths
- Multicentre, double-blind, placebo-controlled randomized phase 3 design
- Stratified block randomization and modified intention-to-treat analysis
Limitations
- Single-country study (China), potentially affecting generalizability
- Subgroup findings may be due to chance; lack of biomarker-guided patient selection
Future Directions: Design immunophenotype-enriched trials of sepsis immunotherapies; evaluate adaptive designs and early biological endpoints to detect subgroup benefits.
OBJECTIVE: To evaluate whether the immunomodulatory drug thymosin α1 reduces mortality in adults with sepsis. DESIGN: Multicentre, double blinded, placebo controlled phase 3 trial. SETTING: 22 centres in China, September 2016 to December 2020. PARTICIPANTS: 1106 adults aged 18-85 years with a diagnosis of sepsis according to sepsis-3 criteria and randomly assigned in a 1:1 ratio to receive thymosin α1 (n=552) or placebo (n=554). A stratified block method was used for randomisation, and participants were stratified by age (<60 and ≥60 years) and centre. INTERVENTIONS: Subcutaneous injection of thymosin α1 or placebo every 12 hours for seven days unless discontinued owing to discharge from the intensive care unit, death, or withdrawal of consent. MAIN OUTCOME MEASURE: The primary outcome was 28 day all cause mortality after randomisation. All analyses were based on a modified intention-to-treat set, including participants who received at least one dose of study drug. RESULTS: Of 1106 adults with sepsis enrolled in the study, 1089 were included in the modified intention-to-treat analyses (thymosin α1 group n=542, placebo group n=547). 28 day all cause mortality occurred in 127 participants (23.4%) in the thymosin α1 group and 132 (24.1%) in the placebo group (hazard ratio 0.99, 95% confidence interval 0.77 to 1.27; P=0.93 with log-rank test). No secondary or safety outcome differed statistically significantly between the two groups. The prespecified subgroup analysis showed a potential differential effect of thymosin α1 on the primary outcome based on age (<60 years: hazard ratio 1.67, 1.04 to 2.67; ≥60 years: 0.81, 0.61 to 1.09; P for interaction=0.01) and diabetes (diabetes: 0.58, 0.35 to 0.99; no diabetes: 1.16, 0.87 to 1.53; P for interaction=0.04). CONCLUSIONS: This trial found no clear evidence to suggest that thymosin α1 decreases 28 day all cause mortality in adults with sepsis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02867267.
2. The Role of Ultrasonographic Assessment of Optic Nerve Sheath Diameter in Prediction of Sepsis-Associated Encephalopathy: Prospective Observational Study.
In a prospective ICU cohort (n=89), serial ONSD ultrasound measurements discriminated SAE with high accuracy; a day-2 cutoff >5.2 mm yielded 93.2% sensitivity and 100% specificity. ONSD correlated with SOFA score and ICU length of stay and was wider in non-survivors.
Impact: Provides a practical, noninvasive bedside tool and actionable cutoff for early SAE detection, enabling risk stratification and timely neuroprotective care.
Clinical Implications: Incorporate ONSD ultrasound into ICU sepsis protocols as an early screen for SAE, especially around day 2, to prioritize neurodiagnostics and optimize sedation, ventilation, and hemodynamic targets.
Key Findings
- Day-2 ONSD >5.2 mm predicted SAE with 93.2% sensitivity and 100% specificity.
- ONSD was significantly higher in the SAE group at baseline and remained higher on days 2, 4, 6, 8, and 10.
- ONSD correlated with SOFA score (r=0.485, P<0.001) and ICU length of stay (r=0.238, P<0.001), and was wider in non-survivors (P<0.001).
Methodological Strengths
- Prospective design with serial standardized ONSD measurements
- Clinical trial registration and clear, objective diagnostic thresholds
Limitations
- Single-center sample with modest size (n=89), limiting generalizability
- No invasive ICP gold-standard validation; observational design susceptible to residual confounding
Future Directions: Multicentre validation with concurrent EEG/ICP monitoring and assessment of ONSD-guided care pathways on neurological outcomes.
BACKGROUND: Ultrasonographic optic nerve sheath diameter (ONSD) is a satisfactory noninvasive intracranial pressure (ICP) monitoring test. Our aim was to evaluate ONSD as an objective screening tool to predict and diagnose ICP changes early in sepsis-associated encephalopathy (SAE). METHODS: Our prospective observational study was conducted on patients with sepsis, and after intensive care unit (ICU) admission, the time to diagnose SAE was recorded, and patients were divided into a non-SAE group including conscious patients with sepsis and a SAE group including patients with sepsis with acute onset of disturbed conscious level. ONSD was measured within 24 h of ICU admission for all patients and then every other day for up to 10 consecutive days until ICU discharge or death. The primary outcome was to compare ONSD measurements of both groups to find if there was a correlation between ONSD and SAE occurrence. RESULTS: Eighty-nine patients with sepsis were divided into a non-SAE group (n = 45) and an SAE group (n = 44). ONSD showed a statistically significant difference at day 0 and a highly significant difference at days 2, 4, 6, 8, and 10. Day 2 ONSD had the best accuracy for predicting SAE, with a cutoff > 5.2 mm (sensitivity of 93.2%, specificity of 100%), a statistically positive correlation with the Sequential Organ Failure Assessment score (r = 0.485, P < 0.001) and ICU length of stay (r = 0.238, P < 0.001), and a statistically significant wider in patients who died compared to those who survived (P < 0.001). CONCLUSIONS: ONSD could be an objective screening method for early diagnosis of SAE, with a cutoff > 5.2 mm. Trial registration NCT05849831 ( https://clinicaltrials.gov/study/NCT05849831 ).
3. Combined detection of monocyte distribution width and procalcitonin for diagnosing and prognosing neonatal sepsis.
In a retrospective neonatal cohort (39 sepsis, 30 non-infectious SIRS), MDW and PCT were elevated in sepsis, and MDW independently predicted 28-day mortality. The combination of MDW and PCT improved diagnostic accuracy (AUC 0.90; 88.2% sensitivity, 88.7% specificity) compared with either alone.
Impact: Offers a pragmatic biomarker combination to enhance early diagnosis and risk stratification in neonatal sepsis, a high-mortality setting with limited rapid diagnostics.
Clinical Implications: Consider integrating MDW with PCT in neonatal sepsis evaluation pathways to improve diagnostic accuracy and identify high-risk infants for closer monitoring and timely therapy.
Key Findings
- MDW, PCT, and CRP were significantly higher in neonatal sepsis (p<0.001).
- MDW independently predicted 28-day mortality and correlated with CRP, PCT, and SNAP scores.
- Optimal cut-offs: MDW 21.3, PCT 1.23 ng/mL, CRP 32.8 mg/L; combined MDW+PCT yielded AUC 0.90 (sensitivity 88.2%, specificity 88.7%).
Methodological Strengths
- Use of ROC analysis with predefined cutoffs and multivariable Cox regression
- Comparative evaluation against non-infectious SIRS controls
Limitations
- Single-center retrospective design with small sample size
- Potential selection bias and lack of external validation
Future Directions: Prospective multicentre validation and integration into decision-support algorithms alongside blood culture and rapid molecular tests.
BACKGROUND: To assess the value of combined Monocyte Distribution Width (MDW) and Procalcitonin (PCT) detection in diagnosing and predicting neonatal sepsis outcomes. METHODS: This retrospective study, conducted from January 2022 to December 2023.A retrospective analysis of 39 neonatal sepsis and 30 non-infectious systemic inflammatory response syndrome (SIRS) cases was conducted. MDW, PCT, and CRP levels were compared. Relationships between variables were analyzed with Pearson correlation and Cox regression models; diagnostic performance was assessed using ROC curves. RESULTS: MDW, PCT, and CRP were significantly elevated in sepsis cases (p < 0.001). In non-survivors, MDW was higher and correlated with CRP, PCT, and SNAP scores. MDW was identified as an independent predictor of 28-day mortality. Optimal MDW, PCT, and CRP cut-offs (21.3, 1.23 ng/ml, 32.8 mg/L) achieved AUCs of 0.80, 0.84, and 0.60, respectively. Combined MDW/PCT detection achieved an AUC of 0.90 with 88.2% sensitivity and 88.7% specificity. CONCLUSION: MDW, especially when combined with PCT, improves diagnostic accuracy for neonatal sepsis management.