Extracorporeal Blood Purification Offers Dual Immunomodulatory Role in Sepsis, Beyond Cytokine Removal

Despite advancements in early detection and supportive care, specific treatments for sepsis remain elusive, with current guidelines primarily focusing on hemodynamic support. Traditional extracorporeal blood purification (EBP) rationales have historically centered on a concentration-dependent hypothesis of cytokine removal. However, emerging evidence suggests this plasma-centric view is insufficient due to complex multicompartmental solute kinetics. A critical gap exists in understanding how EBP truly impacts the profound immune dysregulation characteristic of sepsis, which transitions from an initial hyperinflammatory 'cytokine storm' to a state of 'immunoparalysis'.

This review proposes a comprehensive mechanistic framework for extracorporeal blood purification (EBP) in sepsis, moving beyond the traditional cytokine removal hypothesis. The authors integrated existing evidence to describe both mediator-directed and cell-directed immunomodulation by EBP. They analyzed how various EBP modalities, including different membrane types and sorbents, interact with the complex pathophysiology of sepsis. The review also highlighted the necessity of integrating theragnostic biomarkers to guide EBP application, aiming to transition towards phenotype-driven approaches for optimizing patient outcomes.

The review established a dual mechanistic framework for extracorporeal blood purification (EBP) in sepsis, encompassing both mediator-directed and cell-directed immunomodulation. Mediator-directed therapies, such as those utilizing AN69ST or PMMA membranes and selective sorbents, aim to reduce the circulating burden of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This directly targets the initial inflammatory triggers. Concurrently, cell-directed interventions, exemplified by PMX-HA (polymyxin B hemoperfusion) and SCD (selective cytapheresis devices), focus on 'reprogramming' activated or exhausted leukocytes. This reprogramming is crucial for restoring immune homeostasis, addressing the later phase of immunoparalysis. The authors emphasize that a transition to precision medicine in sepsis necessitates the integration of theragnostic biomarkers. These include markers like mHLA-DR (monocytic HLA-DR expression), NLR (neutrophil-to-lymphocyte ratio), and NETosis markers, which are vital for identifying specific immune endotypes. This allows for tailored EBP strategies.

EBP must evolve from device-agnostic applications to phenotype-driven approaches that optimize the timing and selection of extracorporeal support to improve clinical outcomes.