Comparative efficacy and safety of immunomodulatory therapies for sepsis: a systematic review and network meta-analysis

Background As a standard therapy, immunotherapy is widely used for sepsis patients. Despite the presence of various immunomodulators, studies comparing their safety and efficacy synthetically are still lacking. Methods Electronic databases (PubMed, Embase, and the Cochrane Library) were searched from inception to March 31, 2025. The primary endpoint assessed was all-cause mortality, whereas secondary outcomes included duration of mechanical ventilation (MV duration), length of intensive care unit (ICU-LOS) and hospital stay (hospital-LOS). Safety was evaluated by monitoring adverse events or serious adverse events (AEs/SAEs). For effect estimation, the risk ratio (RR) and mean difference (MD) with a 95% confidence interval (95% CI) were utilized. The network meta-analysis was executed via the ‘BUGSnet’ and ‘JAGS’ packages within R 4.4.2. Interventions were ranked by surface under the cumulative ranking curve (SUCRA) values. The risk of bias was assessed with the Cochrane RoB tool, and evidence quality was graded via GRADE. Results A total of 76 randomized controlled trials (RCTs) involving 22,194 patients were included. Ulinastatin had the most favorable effect on reducing all-cause mortality [RR 0.37 (0.22, 0.59)]. Ulinastatin plus thymosin-α1, polyunsaturated fatty acids (PUFA), and monoclonal antibody (MAb) also lowered mortality versus other treatments [RRs 0.65 (0.54, 0.77), 0.74 (0.61, 0.91), 0.92 (0.84, 0.99)]. Ulinastatin plus thymosin-α1 reduced ICU-LOS [MD −2.91 (−5.39, −0.44)], while PUFA shortened hospital-LOS [MD −20.55 (−39.81, −0.51)]. Both ulinastatin alone and with thymosin-α1 shortened MV duration [MDs − 4.43 (−8.32, −0.49) and −1.86 (−3.14, −0.41)]. Ulinastatin (with/without thymosin-α1) and PUFA were linked to fewer SAEs. Conclusion On the basis of the findings of this first network meta-analysis evaluating a broad spectrum of immunomodulators for sepsis, ulinastatin (alone or in combination with thymosin-α1), PUFA, and MAb have significant potential for reducing mortality and improving other clinical outcomes. However, the certainty of evidence for most comparisons remains low, which underscores the need for large-scale, direct-comparison RCTs to validate these findings and guide clinical practice.