Assessment of immune organ dysfunction in critical illness: utility of innate immune response markers

Abstract

In critically ill patients, organ dysfunctions are routinely assessed, monitored, and treated. Mounting data show that substantial critical illness-induced changes in the immune system can be observed in most ICU patients and that not only “hyper-inflammation” but also persistence of an anti-inflammatory phenotype (as in sepsis-associated immunosuppression) is associated with increased morbidity and mortality. Despite common perception, changes in functional immunity cannot be adequately assessed by routine inflammatory biomarkers such as C-reactive protein, procalcitonin, or numerical analysis of leukocyte (sub)-counts. Cytokines appear also not suited due to their short half-life and pleiotropy, their unexclusive origin from immune cells, and their potential to undergo antagonization by circulating inactivating molecules. Thus, beyond leukocyte quantification and use of routine biomarkers, direct assessment of immune cell function seems required to characterize the immune systems’ status. This may include determination of, e.g., ex vivo cellular cytokine release, phagocytosis activity, and/or antigen-presenting capacity. In this regard, standardized flow-cytometric assessment of the major histocompatibility-II complex human leukocyte antigen (-D related) (HLA-DR) has gained particular interest. Monocytic HLA-DR (mHLA-DR) controls the interplay between innate and adaptive immunity and may serve as a “global” biomarker of injury-associated immunosuppression, and its decreased expression is associated with adverse clinical outcomes (e.g., secondary infection risk, mortality). Importantly, recent data demonstrate that injury-associated immunosuppression can be reversed—opening up new therapeutic avenues in affected patients. Here we discuss the potential scientific and clinical value of assessment of functional immunity with a focus on monocytes/macrophages and review the current state of knowledge and potential perspectives for affected critically ill patients.

Monocytic HLA-DR expression kinetics in septic shock patients with different pathogens, sites of infection and adverse outcomes

“…Overall, we demonstrate that patients with a decreasing mHLA-DR expression over time have the highest occurrence of secondary infections and mortality rate. This is in accordance with literature, as our group and others have previously described the relationship between decreased or non-recovering mHLA-DR expression and unfavourable outcome [6,7,[16][17][18][19][20][21]. However, to the best of our knowledge, we are the first to apply unsupervised trajectory modelling.…”

“…Thirteen percent of the patients developed a secondary infection, which occurred after 10 [7][8][9][10][11][12][13][14][15][16][17][18][19][20] days. The sites of secondary infections are listed in Supplementary Table 3.…”

Early immunosuppression was associated with poor prognosis in elderly patients with sepsis: secondary analysis of the ETASS study

“…According to previous study, early immune status was defined as the immune status within 48 hours after onset of sepsis [19]. Immune status was measured by the expression of mHLA-DR because of its proven value in septic patients [22]. Therefore, only those patients with mHLA-DR measured within 48 hours after onset of sepsis was enrolled in this study (273/361).…”

Immune biomarker-based enrichment in sepsis trials

“…In the study by Anderson et al, "immunocompetency" in sepsis patients was defined using clinical criteria. However, it seems that immunocompetency, i.e., (functional) immune phenotype, cannot be assessed by predominantly clinical parameters and should be based on comprehensive functional immune markers (e.g., mHLA-DR expression [2][3][4]) in order to identify individuals who would benefit most from a given intervention.…”