Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3K␦. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P ‫؍‬ .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P ‫؍‬ .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection. (Blood. 2011;117(19):5178-5188) IntroductionThe systemic inflammatory response syndrome (SIRS) is classically characterized by profound immune activation, accompanying massive cytokinemia and organ damage. 1,2 However, SIRS is accompanied by a counter-regulatory immune suppression sometimes termed the compensatory anti-inflammatory response syndrome (CARS). 3 This relative immune suppression is considered important for effective resolution of inflammation but may extend to maladaptive counter-regulatory anti-inflammatory responses. 4,5 The consequences of impaired immune function include enhanced susceptibility to nosocomial infection 6 or death from sepsis. 7 Neutrophils are the major front-line cellular defense against bacterial pathogens, and acquired defects in neutrophil function have been identified in both animal and human sepsis 8,9 as well as sterile SIRS. 10,11 However, the mediators driving these defects, and the mechanisms involved, remain uncertain.Animal studies have implicated uncontrolled activation of the complement system in the pathogenesis of sepsis and sterile SIRS. [12][13][14] The key components mediating vasodilatation and vascular leak-the hallmarks of septic shock-are the anaphylatoxins. These are activated forms of complement factors 3 (C3a) and 5 (C5a). 14,15 Animal models of sepsis have also implicated C5a in neutrophil dysfunction. 8 Because of the rapid clearance (2-to 3-minute half life) of C5a from the circulation, measurement of plasma concentrations gives an imprecise account of neutrophil expos...

Dysfunctions of T-cells, monocytes, and neutrophils predict acquisition of nosocomial infection, and combine additively to stratify risk of nosocomial infection in the critically ill.