Does GM-CSF restore effective neutrophil function in critically ill patients?

Abstract

Nosocomial infection is an increasing problem worldwide associated with significant morbidity and mortality in addition to heightened healthcare costs. The problem is even greater on the intensive care unit (ICU) where up to 20 of patients develop a secondary infection during their admission. In an era of increasing antibiotic resistance alternative strategies to prevent nosocomial infection must be sought. The intensive care population are recognised to be at high risk of developing immune dysfunction during their critical illness and this has been shown to be associated with an increased risk of the development of ICU acquired infection (ICUAI). The neutrophil, in particular, is key in terms of the host response to bacterial and fungal infections and impairments in neutrophil function have been demonstrated in critically ill patients. Granulocyte-macrophage colony-stimulating factor has been shown to improve the phagocytic function of impaired neutrophils ex-vivo and has previously been demonstrated to restore immune competent levels of monocyte HLA-DR expression in critically ill patients. If GM-CSF were demonstrated to restore neutrophil phagocytic function in critically ill patients in whom its known to be impaired it may have a role in preventing the development of ICUAI. Our initial study sought to validate neutrophil CD88 expression as a surrogate marker for phagocytic function. The dose finding study which followed aimed to determine the optimum dose and duration of GM-CSF to be carried forward to a randomised controlled trial. Finally, the randomised controlled trial sought to investigate the hypothesis that GM-CSF could restore effective neutrophil function in critically ill patients. While no significant difference was seen in our primary endpoint of neutrophil phagocytic capacity, on day 2 following administration of GM-CSF, we believe a small but true biological effect was observed suggesting further study is warranted to investigate whether GM-CSF could reduce the risk of ICUAI.