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.
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.
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.