IgM-enriched immunoglobulin shows directionally favorable but statistically inconclusive results for short-term mortality in sepsisIgM Therapy for Sepsis Shows Promise but Not Proof

OBJECTIVES: To evaluate randomized adult evidence on adjunctive immunoglobulin M (IgM)-enriched immunoglobulin for sepsis and septic shock, with emphasis on short-term mortality, endpoint heterogeneity, statistical robustness, and harms reporting. DATA SOURCES: MEDLINE, PubMed, Embase, CENTRAL, and Web of Science were searched from inception to September 2025. Reference lists of eligible articles and relevant reviews were screened, forward citation searching was performed, and study registers were checked for additional records. STUDY SELECTION: Randomized controlled trials enrolling adults with sepsis, severe sepsis, or septic shock were eligible when they evaluated an IgM-enriched immunoglobulin preparation in addition to standard care and reported extractable mortality or clinically relevant outcomes. The protocol-concordant core synthesis included English-language adult Pentaglobin trials with extractable short-term mortality data. Two post hoc extensions were labeled explicitly: a language-inclusive Pentaglobin sensitivity analysis and an exploratory formulation-class analysis incorporating the phase II Concentrated IgM for Application (CIGMA) trimodulin trial. DATA EXTRACTION: Two reviewers independently screened records, assessed full texts, extracted study characteristics, endpoint timing, mortality events, and reported adverse events, and resolved disagreements by discussion or third-reviewer adjudication. Risk of bias was assessed with Cochrane Risk of Bias 2 tool for randomized trials, and certainty was judged with the Grading of Recommendations Assessment, Development, and Evaluation principles. DATA SYNTHESIS: Six English-language randomized Pentaglobin trials with extractable short-term mortality data (411 participants) contributed to the protocol-concordant core synthesis. The primary pooled estimate was directionally favorable but statistically inconclusive (odds ratio [OR], 0.65; 95% CI, 0.39-1.07; I2 = 9%). Restriction to exact 28-day mortality also remained inconclusive (OR, 0.84; 95% CI, 0.50-1.43; I2 = 0%). An alternative risk-ratio model was similarly nonsignificant (risk ratio, 0.76; 95% CI, 0.55-1.06; I2 = 0%). Statistically significant estimates arose only in exploratory post hoc analyses: the language-inclusive Pentaglobin sensitivity analysis (OR, 0.57; 95% CI, 0.34-0.95; I2 = 16%) and the exploratory formulation-class model including CIGMA (OR, 0.64; 95% CI, 0.43-0.94; I2 = 5%). Safety reporting was incomplete in most Pentaglobin reports. CONCLUSIONS: Current randomized adult evidence does not justify routine use of IgM-enriched immunoglobulin in unselected sepsis or septic shock. Direct Pentaglobin evidence remains statistically inconclusive, whereas statistically significant estimates appear only after exploratory expansion to historical or indirect formulation-level evidence. Efficacy remains unproven, but the recurrent direction of effect supports a modern, adequately powered, phenotype-guided trial with standardized day-28 mortality and rigorous safety assessment.