Past, Present, and Future of Augmentation of Monocyte Function in the Surgical Patient

Background: Patients who survive the early phases of major sepsis and trauma can have greater susceptibility to nosocomial infection later. One cause may be impaired monocyte function, which can leave the patient at risk of overwhelming sepsis and multi-organ dysfunction. Efforts to target this immune defect have been fraught with challenges, with many questions unanswered. We summarized the past and current and likely future therapeutic approaches to augmentation of monocyte function in the surgical patient. Methods: A literature search was conducted using PubMed to determine the evidence to date for immunoadjuvant therapy specifically for monocyte impairment. The search terms were "monocyte," "immunoparalysis," "tolerance," and "deactivation" cross-referenced with "trauma," "major surgery," and "sepsis." We supplemented our search with "interferon-gamma," "granulocyte colony-stimulating factor" (G-CSF), and "granulocytemacrophage colony-stimulating factor" (GM-CSF), known agents used for this purpose. We limited our findings to clinical trials in human beings. Relevant currently registered trials relating to impaired monocyte function also were included. Results: Interferon-gamma appears to be the most commonly studied therapeutic agent to augment monocyte function, followed in decreasing order by GM-CSF and G-CSF. Studies were heterogeneous, generally underpowered, and enrolled few target patients with documented monocyte impairment. Finally, current studies are focusing on personalized therapy in order to treat those with monocyte impairment, with attention to programmed cell death protein 1 (PD-1) and programmed cell death ligand (PD-L1) as both markers and therapeutic targets. Conclusion: Early studies have been promising in identifying patients who are likely to benefit from monocyte augmentation; i.e., those with low HLA-DR or ex-vivo tumor necrosis factor (TNF)-alpha production. The surgeon remains incompletely equipped to enhance monocyte function consistently and specifically in order to reduce the mortality rate. Although there is little evidence to support the routine use of any of these immunotherapies, the issues of patient selection, timing of administration, and treatment duration have hampered any true answers to this important clinical problem. The challenge remains in identifying the right patients, at the right time, to receive the right therapy.