Sepsis‐induced immune alterations monitoring by flow cytometry as a promising tool for individualized therapy

Abstract

Septic syndromes remain a major although largely under-recognized health care problem and represent the first cause of mortality in intensive care units. While sepsis has, for long, been solely described as inducing a tremendous systemic inflammatory response, novel findings indicate that sepsis indeed initiates a more complex immunologic response that varies over time, with the concomitant occurrence of both pro-and anti-inflammatory mechanisms. As a resultant, after a short proinflammatory phase, septic patients enter a stage of protracted immunosuppression. This is illustrated in those patients by reactivation of dormant viruses (CMV or HSV) or infections due to pathogens, including fungi, which are normally pathogenic solely in immunocompromised hosts. Although mechanisms are not totally understood, these alterations might be directly responsible for worsening outcome in patients who survived initial resuscitation as nearly all immune functions are deeply compromised. Indeed, the magnitude and persistence over time of these dysfunctions have been associated with increased mortality and health-care associated infection rate. Consequently, new promising therapeutic avenues are currently emerging from those recent findings such as adjunctive immunostimulation (IFN-g, GM-CSF, IL-7, anti-PD1/L1 antibodies) for the most immunosuppressed patients. Nevertheless, as there is no clinical sign of immune dysfunctions, the prerequisite for such therapeutic intervention relies on our capacity in identifying the patients who could benefit from immunostimulation. To date, the most robust biomarkers of sepsis-induced immunosuppression are measured by flow cytometry. Of them, the decreased expression of monocyte HLA-DR appears as a "gold standard." This review reports on the mechanisms sustaining sepsis-induced immunosuppression and its related biomarkers measurable by flow cytometry. The objective is to integrate the most recent facts in an up-to-date account of clinical results, flow cytometry aspects as well as issues in results standardization for multicenter studies. V C 2015 International Clinical Cytometry Society

Global analysis of glycoproteins identifies markers of endotoxin tolerant monocytes and GPR84 as a modulator of TNFα expression

“…Downregulation of HLA class II genes in tolerant monocytes was reported in in vitro models, in reprogrammed monocytes from cystic fibrosis patients, in patients with septic shock, and in tumor-tolerized monocytes 20, 28, 31, 59 and is considered as a hallmark of the reduced antigen presentation capacity of monocytes in the tolerant cell state. Decreased expression of HLA-DR molecules, the current gold standard for the detection of monocyte tolerance by cell surface expressed proteins on monocytes 60 , was found in the CD14 + monocyte data set, though, without statistical significance. This indicates that the in vitro analysis of purified monocytes in culture as a model for monocyte phenotyping in the tolerant state might not reflect all proteomic changes that can occur in vivo , when the diversity of soluble mediators released by other myeloid cells or tissues react on peripheral blood monocytes.…”

The immune system's role in sepsis progression, resolution, and long‐term outcome

“…Reduced monocyte HLA‐DR expression and failure of HLA‐DR expression restoration are indicative of immune paralysis, the susceptibility to opportunistic infections, and overall sepsis outcome . In addition, the decreased expression of monocyte HLA‐DR, the most robust biomarker of sepsis‐induced immune suppression, is easily measured by flow cytometry analysis which is quick, easy, and affordable . In a recent report, investigators were able to demonstrate that monocyte PD‐L1 expression after 3‐4 days of sepsis was associated with risk stratification and mortality.…”

Does major surgery induce immune suppression and increase the risk of postoperative infection?

“…Encouragingly there is now increasing evidence that quantifying the host response using flow cytometry in the clinical setting practice may have value in terms of risk stratification for postoperative nosocomial infections and also to monitor the response to treatment [57]. This technology is rapid, easy to process and a wide variety of cell surface markers are available [57].…”

“…This technology is rapid, easy to process and a wide variety of cell surface markers are available [57]. In the case of mHLA-DR, the use of a standardized assay and protocol [58] removes inter-laboratory variation [59], thereby allowing treatment thresholds to be defined.…”