Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis

Abstract

Objective: To evaluate the effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on immunoparalysis as defined by a sustained decrease of HLA-DR expression on monocytes in patients with severe sepsis.

Design: Prospective, non-randomised observational study.

Setting: Two anaesthesiological intensive care units of a university hospital.

Intervention: Administration of a daily dose of 5 micro g/kg rhGM-CSF over a period of 3 days.

Patients: Nine consecutive patients with severe sepsis and a documented HLA-DR expression on peripheral monocytes of less than 150 mean fluorescence intensity (MFI) over a period of at least 48 h prior to intervention.

Measurements and results: Mean MFI was 69.4+/-13.2 24 h before and 56.7+/-8.2 on the day of the administration of 5 micro g/kg rhGM-CSF. Within 24 h a significant increase of HLA-DR expression to a mean of 327.7+/-78.8 MFI was observed in all patients. This increase was maintained on days 2-10. It was accompanied by a significant rise in white blood count. The ex vivo TNF-alpha production in whole blood after lipopolysaccharide (LPS)-stimulation increased significantly from a mean of 82+/-29.2 pg/ml to 793+/-546.8 pg/ml. Apart from febrile reactions in two patients, no side effects were recorded. No increases of pro-inflammatory markers (IL-6, C-reactive protein, LPS-binding protein, procalcitonin) were observed. SOFA values before and after rhGM-CSF did not differ significantly. The mortality rate was 33%.

Conclusion: This preliminary study demonstrates that rhGM-CSF upregulates HLA-DR expression on monocytes in septic patients with multi-organ dysfunction. Moreover, with the concomitant increase of the ex vivo whole blood TNF-alpha response, this upregulation of a monocytic activation marker is paralleled by a functional recovery.