Precision Immunotherapy for Sepsis

Abstract

Decades of sepsis research into a specific immune system-targeting adjunctive therapy have not resulted in the discovery of an effective compound. Apart from antibiotics, source control, resuscitation and organ support, not a single adjunctive treatment is used in current clinical practice. The inability to determine the prevailing immunological phenotype of patients and the related large heterogeneity of study populations are regarded by many as the most important factors behind the disappointing results of past clinical trials. While the therapeutic focus has long been on immunosuppressive strategies, increased appreciation of the importance of sepsis-induced immunoparalysis in causing morbidity and mortality in sepsis patients has resulted in a paradigm shift in the sepsis research field towards strategies aimed at enhancing the immune response. However, similar to immunosuppressive therapies, precision medicine is imperative for future trials with immunostimulatory compounds to succeed. As such, identifying those patients with a severely suppressed or hyperactive immune system who will most likely benefit from either immunostimulatory or immunosuppressive therapy, and accurate monitoring of both the immune and treatment response is crucial. This review provides an overview of the challenges lying ahead on the path towards precision immunotherapy for patients suffering from sepsis.

Keywords: biomarkers; hyperinflammation; immunoparalysis; immunostimulatory therapy; immunosuppressive therapy; precision medicine; sepsis.

Figure 1

Clinical consequences of hyperinflammation and immunoparalysis to selected tissues. ARDS, acute respiratory distress syndrome; LSEC, liver sinusoidal endothelial cells; MDSC, myeloid-derived suppressor cells; RTEC, renal tubule epithelial cell; M-cell, microfold cell; TPN, total parenteral nutrition; HSPC, hematopoietic stem and progenitor cells.