Loss of evolutionary conserved GM-CSF-dependent signature in pulmonary macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment (microarray). Loss of evolutionary conserved GM-CSF-dependent signature in pulmonary macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment (microarray)

Alveolar GM-CSF is required for monocytes to differentiate into alveolar macrophages (AM) that control alveolar homeostasis and dampen inflammation. By mapping cross-species AM development stages to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of proinflammatory macrophages. In a multi-center, open-label, randomized, controlled trial in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides rationale for further testing of inhaled GM-CSF as non-invasive treatment to improve alveolar gas exchange and simultaneously boost anti-viral immunity in COVID-19 Overall design: Compare microarrays of GM-CSF KO mice and microarrays covering the AMF development: Fetal liver monocyte (E15.5), Bone Marrow monocyte (adult), lung macrophage on E15.5, E17.5 and E19.5, Pre-AMF on day of birth, AMF on day 9 after birth and adult AMF to identify a GM-CSF gene signature. Some of these microarrays were already published in GSE117081 and GSE76999.