Developmental Clinical Studies: Does GM-CSF restore effective neutrophil function in critically ill patients?

Patients admitted to intensive care units (ICUs) are at very high risk of developing new infections in hospital. These hospital infections are commonly caused by bacteria that do not respond to antibiotics and are often termed ?superbugs?. Patients in ICU who develop new infections are more likely to die, or to have longer stays in ICU. Despite a variety of approaches aiming to prevent these hospital infections, they remain unacceptably common in the ICU.

We have recently shown that the key blood cells (called neutrophils) mainly responsible for fighting bacteria commonly fail to work efficiently in ICU patients. This seems to contribute to the increased risk of infection. Adding a drug (GM-CSF) to such non-functioning neutrophils in the laboratory invariably improves their function. This suggests that, if high-risk patients with poorly functioning neutrophils could be identified, GM-CSF may be able to prevent infections. However GM-CSF has never been specifically targeted to ICU patients with non-functioning neutrophils before. The next crucial step in establishing whether GM-CSF may prevent infections in ICU is therefore to test whether GM-CSF improves the function of neutrophils in high-risk patients.

Our aim is therefore to identify ICU patients who have poorly functioning neutrophils, using a simple laboratory test. The patients will be randomly assigned to receive either GM-CSF or a dummy drug (placebo). Neither the patient nor the doctors will be aware whether GM-CSF or placebo has been given until after the project is completed, when the research team will analyse the results. This type of study is called a randomised placebo controlled double blind trial and is widely accepted to be the best way to find out if a treatment really works or not. In this way we shall establish whether GM-CSF improves the function of neutrophils. If this ?proof of concept? study does demonstrate benefit for GM-CSF, it would rapidly pave the way for large studies establishing if GM-CSF can prevent development of infection in ICU when targeted specifically at patients whose neutrophils function poorly.

Despite introduction of multiple preventive measures, nosocomial infection rates remain unacceptably high, particularly in the intensive care unit (ICU) where 20-40% of patients acquire new nosocomial infections. Novel strategies are therefore urgently required. The neutrophil is the key cellular effector for clearance of bacterial and fungal pathogens. We have demonstrated that: impaired neutrophil phagocytosis is common in ICU patients; patients with impaired neutrophil phagocytosis in ICU are at significantly increased risk of nosocomial infection; and granulocyte-macrophage colony-stimulating factor (GM-CSF) applied to patients? impaired neutrophils ex vivo restores effective phagocytosis. If subcutaneous (s/c) GM-CSF, targeted to high risk patients with proven neutrophil dysfunction, also restored effective phagocytosis, GM-CSF would be well positioned for comprehensive assessment/development as a novel measure to prevent nosocomial infection in ICU. GM-CSF has never been evaluated as a therapy specifically targeted to critically ill patients with neutrophil dysfunction in the ICU.
We therefore propose a) to determine the optimal dose/duration of GM-CSF in this specific setting in order b) to perform the first proof of concept, double-blind randomised controlled trial of s/c GM-CSF specifically targeting critically ill patients with proven neutrophil dysfunction, and therefore at high risk of nosocomial infection. The primary endpoint will be neutrophil phagocytic capacity. A proven beneficial effect for GM-CSF would rapidly pave the way for larger studies assessing its capacity to prevent nosocomial infections in the ICU.