SEPTIC

Does GM-CSF compared to placebo improve outcomes in a high-risk subset of patients admitted to ICU with sepsis?

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Although sepsis has classically been described as an inflammatory condition, the new sepsis definition recognises that it is a more diverse, dysregulated host response. Many septic patients manifest impaired immune responsiveness and this is associated with an increased risk of mortality and secondary infection. This sepsis-associated immune paresis is reflected in impaired function of circulating and tissue-migrated leukocytes, and in genomic signatures associated with profound immune dysfunction. Arguably the best-characterised example of sepsis-associated immune cell dysfunction is the reduction in circulating monocyte HLA-DR, which has consistently been associated with adverse outcomes. 

 

Accelerated lymphocyte apoptosis and impaired bacterial killing by neutrophils are also well described. Clear evidence for leukocyte dysfunction in sepsis has stimulated interest in immune-stimulatory therapies, with a view to reversing immune paresis. GM-CSF is particularly attractive in this regard, given its known effects on stimulating both neutrophil and monocyte production and function, and the considerable clinical experience of its use in the treatment of chemotherapy-induced myelo ablation in acute myeloid leukaemia. GM-CSF has been studied in small RCTs in sepsis, where it has proved to be safe, and associated with a rapid and sustained improvement in monocyte HLA DR.

 

In the broader ICU context, GM-CSF has also been found to be 18mmune-stimulatory and well tolerated in respiratory failure and in patients at highest risk of ICU-acquired infection. Importantly, severe critical illness itself drives impairment of neutrophil function, lymphocyte apoptosis, reduced monocyte HLA-DR and an elevation in regulatory T cells that are collectively associated with a significant increase in ICU-acquired infection.

 

GM-CSF restores neutrophil function ex vivo.

 

GM-CSF has been demonstrated to improve monocyte HLA-DR and the proportion of patients with functional neutrophils in a recent RCT.

 

While GM-CSF studies in ICU to date have not been designed to assess mortality, the SEPTIC investigators have conducted a meta-analysis of the data from the studies described above and a trend is seen toward reduced mortality. This supports the need for a larger trial powered for mortality of GM CSF in sepsis.