From an immunological point of view, the pathophysiology of septic shock combines a pro-inflammatory response induced by pathogens or their derivative molecules with an associated anti-inflammatory response that finally results in a state of profound and pronounced immunosuppression in a significant subset of patients [1].

Sepsis-induced immunosuppression involves both the innate and adaptive immune responses resulting in numerous dysfunctions including depletion of the T cell repertoire, lymphopenia (mainly due to apoptosis), and increased circulating regulatory T cells; along with myeloid cell alterations such as decreased expression of HLA-DR on the surface of monocytes (mHLA-DR) and increased myeloid-derived suppressor cells (MDSC). At the soluble mediator level, increased production of various inhibitory mediators has been repeatedly observed. The occurrence of sepsis-induced immunosuppression is reported to be associated with an increased risk of nosocomial infections, longer stay in intensive care, and increased mortality [[2], [3], [4], [5]].

Interestingly, existing treatments can be used to counteract sepsis-induced immunosuppression [6]. Among these, granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to reactivate immune defenses, activate neutrophil, as well as macrophage proliferation, differentiation, and phagocytic capacity. It may also restore immune homeostasis in the lung with acute lung injury post COVID-19, and promote lung repair mechanisms in such patients [[7], [8], [9], [10]]. A meta-analysis investigating the effects of granulocyte colony-stimulating factor (G-CSF) and GM-CSF in septic shock found a beneficial effect on infection reversal rates without an effect on mortality [11]. In addition, in several small trials GM-CSF lowered the duration of mechanical ventilation, severity of the patient, and the length of intensive care unit (ICU) as well as hospital stay [[12], [13], [14]]. However, according to the precision medicine approach, and considering the well-known heterogeneity of septic patients (including immune trajectories), a prerequisite for the use of immunostimulant drugs is the identification of the most immunosuppressed patients. Decreased mHLA-DR is accepted as a marker to characterize sepsis-induced immunosuppression [15].

In the present trial, we therefore hypothesized that, in severe sepsis or septic shock patients presenting with immunosuppression defined by low mHLA-DR, the administration of GM-CSF would reduce the occurrence of ICU-acquired infections.