Restoration of Monocyte HLA-DR in Sepsis: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Introduction. Sepsis usually develops into an immunosuppressive state characterized by a reduction in monocyte HLA-DR expression. There have been many immunomodulatory and extracorporeal treatment options proposed to overcome this malfunction, but their overall effectiveness has not been determined.Methods. Randomized controlled trials were meta-analysed and systematically reviewed to evaluate therapies to restore monocyte HLA-DR expression in patients with sepsis in the adult population. Trials reporting quantitative post-treatment monocyte HLA-DR at an early follow-up time point were included. A random-effects model was used to pool standardized mean differences to control the heterogeneity among assay platforms.Results. Seven randomized clinical trials included eight treatment groups to be analyzed (a total of 329 subjects). All interventions (cytokine-based interventions, granulocyte-macrophage colonystimulating factor, interferon-γ, extracorporeal modalities, polymyxin-B hemoperfusion, continuous hemofiltration, hemofiltration–hemoadsorption) resulted in an increase in monocyte HLA-DR expression compared to control conditions. The overall effect size was large and statistically significant (SMD = 1.79, 95% CI: 1.18 to 2.40). Heterogeneity was high (I² ≈ 78%); however, leave-one-out sensitivity analyses demonstrated the robustness of the results, and the direction of the effect was always positive across all studies.Conclusions. Immunomodulatory and extracorporeal therapies consistently increase monocyte HLA-DR expression in sepsis, supporting the reversibility of sepsis-induced immunosuppression, with cytokine-based therapies showing the strongest effects. HLA-DR emerges as a key biomarker and therapeutic target, but evidence is limited by small, heterogeneous studies and reliance on surrogate endpoints. Larger, standardized trials with patientcentred outcomes are needed to determine whether HLA-DR restoration improves survival.