Early treatment with inhaled GM-CSF improves oxygenation and anti-viral immunity in COVID-19 induced lung injury – a randomized clinical trial

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) instructs monocytes to differentiate into alveolar macrophages (AM) that preserve lung homeostasis. By comparing AM development in mouse and human, we discovered that COVID-19 patients showed marked defects in GM-CSF-dependent AM instruction. The multi-center, open-label, randomized, controlled SARPAC-trial evaluated the efficacy and safety of 5 days of inhalation of rhu-GM-CSF (sargramostim, Leukine®) in 81 non-ventilated patients with COVID-19 and hypoxemic respiratory failure identified by PaO2/FiO2 ratio < 350mmHg. At day 6, more patients in the sargramostim group experienced at least 25% improvement in oxygenation compared with the standard of care group. Higher numbers of circulating class-switched B cells and effector virus-specific CD8 lymphocytes were found in the sargramostim group. Treatment adverse events, including signs of cytokine storm, were not different between active and control group. This proof-of-concept study demonstrates the feasibility and safety of inhaled GM-CSF in restoring alveolar gas exchange, while simultaneously boosting anti-COVID-19 immunity. ClinicalTrials.gov (NCT04326920).

GM-CSF: Orchestrating the Pulmonary Response to Infection

“…Clinical trials of immune modulators for the treatment of COVID-19 should include prospective immunophenotyping and/or subject stratification based on cell counts, immune function assays, cytokine levels, or other markers of inflammation ( Hall et al, 2020 ). Clinical trials are currently underway to evaluate sargramostim in patients with COVID-19 ( Table 2 ) ( Bosteels et al, 2021 ; ClinicalTrials.Gov, 2020c ; ClinicalTrials.Gov, 2020d ; ClinicalTrials.Gov, 2020f ; ClinicalTrials.Gov, 2020i ; ClinicalTrials.Gov, 2021 ). Preclinical studies suggest that sargramostim administration may improve lung function by strengthening the alveolar wall and enhancing viral clearance.…”

“…• Inhaled sargramostim associated with boosted B-cell responses and SARS-CoV2-specific CD8 + T-cell responses Bosteels et al (2021) …”

“…However, lung macrophages in COVID-19 murine models are characterized by the loss of GM-CSF–mediated instruction that drives AM development, resulting in enrichment of lymphocytes, monocytes and neutrophils and depletion of macrophages in the lung ( Bosteels et al, 2021 ). In COVID-19, instead of lung monocytes developing into AMs with sufficient GM-CSF signal, they develop into proinflammatory CD163 + hemophagocytic macrophages.…”

“…In a small clinical study, inhaled sargramostim (yeast-derived rhu GM-CSF) significantly improved oxygenation ( p = 0.0035) without side effects in patients with severe ARDS ( Herold et al, 2014 ), demonstrating GM-CSF is well-tolerated in the alveolar space. Given the beneficial role of inhaled recombinant GM-CSF in reducing mortality in preclinical pneumonia studies, inhaled sargramostim is under investigation to treat patients with COVID-19 ( Table 2 ) ( Huang et al, 2010 ; Huang et al, 2011 ; Bosteels et al, 2021 ; ClinicalTrials.Gov, 2020c ; ClinicalTrials.Gov, 2020d ; ClinicalTrials.Gov, 2020f ; ClinicalTrials.Gov, 2021 ).…”

“…In the multi-center, open-label, randomized, controlled SARPAC trial, 81 non-ventilated hospitalized COVID-19 patients with acute hypoxemic respiratory failure (oxygen saturation below 93% on ≥ 2 L oxygen per minute or a ratio of the partial pressure of oxygen [PaO 2 ] to the fraction of inspired oxygen [FiO 2 ; P/F ratio] below 350 mmHg) the efficacy and safety of 5 days of inhaled sargramostim (125 μg/m 2 twice daily) with standard of care (SOC) vs. SOC alone were assessed at day 6 ( Bosteels et al, 2021 ). More patients in the sargramostim group experienced at least 25% improvement in oxygenation from baseline by day 6 compared with the standard of care group (62.9 vs 39.5%, p = 0.0459).…”