Infectious Disease · Medical Literature
IgM-Enriched Immunoglobulin As Adjunctive Therapy in Adult Sepsis and Septic Shock: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Abstract
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. 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. 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. 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. 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. 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.
Clinical relevance
Adjunctive IgM-enriched immunoglobulin (Pentaglobin) has been used off-label in sepsis and septic shock based on biological plausibility and small trial signals, yet no adequately powered RCT exists to guide practice. This systematic review and meta-analysis synthesizes the totality of adult randomized evidence—411 participants across six English-language trials—to rigorously evaluate whether a mortality benefit is truly established. The findings are immediately relevant given ongoing interest in immune-modulating adjuncts for sepsis and the risk of premature adoption of unproven therapies in critically ill patients.
Key findings
1. Protocol-concordant core meta-analysis (6 English-language Pentaglobin RCTs; n = 411): pooled OR for short-term mortality 0.65 (95% CI, 0.39–1.07; I² = 9%) — directionally favorable but statistically inconclusive (p > 0.05). 2. Restriction to trials reporting exact 28-day mortality: OR 0.84 (95% CI, 0.50–1.43; I² = 0%) — similarly inconclusive with no heterogeneity. 3. Alternative risk-ratio model (same core trials): RR 0.76 (95% CI, 0.55–1.06; I² = 0%) — nonsignificant across all parameterizations. 4. Language-inclusive Pentaglobin sensitivity analysis (post hoc): OR 0.57 (95% CI, 0.34–0.95; I² = 16%) — first statistically significant estimate, but derived only after exploratory expansion to non-English trials. 5. Exploratory formulation-class analysis incorporating the phase II CIGMA (trimodulin) trial (post hoc): OR 0.64 (95% CI, 0.43–0.94; I² = 5%) — significant but reliant on indirect, heterogeneous formulation-level evidence. 6. Safety reporting was incomplete in the majority of included Pentaglobin reports, precluding reliable harms quantification (NNH not calculable); risk of bias assessment performed using Cochrane RoB 2 with certainty graded per GRADE principles.
Practice implications
Current randomized adult evidence does not support routine or unselected use of IgM-enriched immunoglobulin (Pentaglobin) as adjunctive therapy in sepsis or septic shock; clinicians should not extrapolate statistically significant signals that emerge only from post hoc, exploratory, or formulation-class analyses to bedside decision-making. The consistent directional trend across all models (OR range 0.57–0.84) suggests biological signal worthy of investigation, but efficacy must be considered unproven until a modern, adequately powered RCT with phenotype-guided patient selection, standardized day-28 mortality as the primary endpoint, and rigorous prospective safety monitoring is completed. Institutions should restrict Pentaglobin use in sepsis to the context of approved clinical trials, and formulary or protocol committees should not endorse routine adjunctive immunoglobulin therapy based on the existing evidence base.