Journal Article Epublish
PubMed: 42769414 DOI: 10.1183/23120541.01795-2025
Inhaled granulocyte-macrophage colony-stimulating factor (molgramostim) as host-directed therapy for pneumonia-related acute respiratory distress syndrome: a multicentre, randomised, placebo-controlled phase 2a trial (GI-HOPE).
ERJ Open Res 12(5)
Authors: Susanne Herold, Tobias Welte, Kai Zacharowski, Patrick Meybohm, Michael Bauer, Jochen Wilhelm, Hans-Dieter Walmrath, Khodr Tello, István Vadász, Matthias Hecker, Christina Malainou, Irina Kuznetsova, Ulrich Matt, Janina Trauth, Werner Seeger, Jürgen Lohmeyer
Affiliations
- Department of Internal Medicine V, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Member of the German Center for Lung Research (DZL), Member of the German Center for Infection Research (DZIF), Giessen, Germany.
- Institute for Lung Health, Justus Liebig University Giessen, Giessen, Germany.
- Excellence Cluster Cardio-Pulmonary Institute, Giessen, Germany.
- Department of Respiratory Medicine, Hannover Medical School (MHH), Hannover, Germany.
- Biomedical Research in End-Stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt/Main, Germany.
- Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany.
- Department for Anesthesiology and Intensive Care Medicine, and Center for Sepsis Control and Care, Jena University Hospital, Member of the German Center for Lung Research (DZL), Jena, Germany.
- Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany.
- Department of Internal Medicine V, Universities of Giessen and Marburg Lung Center, Justus Liebig University, Member of the German Center for Lung Research (DZL), Member of the German Center for Infection Research (DZIF), Giessen, Germany. Institute for Lung Health, Justus Liebig University Giessen, Giessen, Germany. Excellence Cluster Cardio-Pulmonary Institute, Giessen, Germany.
Abstract
BACKGROUND
Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances pulmonary host defence and promotes re-establishment of alveolar barrier function. We investigated the safety, feasibility and efficacy of nebulised recombinant human (rh)GM-CSF (molgramostim) in pneumonia-related acute respiratory distress syndrome (ARDS).
METHODS
In this multicentre, randomised, double-blind, parallel-group, placebo-controlled, investigator-initiated phase 2a trial, patients were randomised to receive nebulised low-dose (150 μg) or high-dose (450 μg) rhGM-CSF or placebo for 3 days. Bronchoalveolar lavage (BAL) was performed before the first dose and after dosing. The primary outcome parameter was the composite GI-HOPE score, representing expression changes of CD80, CD86, CD206 and human leukocyte antigen (HLA)-DR on alveolar macrophages after dosing compared to baseline. Secondary outcomes included oxygenation, Sequential Organ Failure Assessment (SOFA) scores and clinical end-points at day 28.
RESULTS
46 participants were randomised, 43 completed treatment (n=15 placebo, n=16 low dose and n=12 high dose), and BAL was performed on 38 participants before and after treatment. Although the composite biological GI-HOPE score did not reach significance (p>0.05), high-dose treatment caused upregulation of HLA-DR and CD206 on alveolar macrophages, indicating deposition in the alveolar compartment and beneficial macrophage activation (HLA-DR: p=0.0406 versus low dose, p=0.1841 versus placebo; CD206: p=0.009 versus low dose, p=0.0179 versus placebo). High-dose rhGM-CSF treatment revealed a favourable profile of oxygenation at the end of analysis compared to time-points before inhalation (p=0.095 and p=0.0175) or compared to the low-dose and placebo groups (p=0.0063 and p=0.0198; visit 13), and was associated with decreased SOFA scores in the high-dose group over time (p=0.0013 and p=0.00023 compared to low dose and placebo). Importantly, inhaled rhGM-CSF did not increase alveolar or systemic inflammation.
CONCLUSION
Inhalation of 450 μg rhGM-CSF was safe, and promoted a favourable profile regarding alveolar macrophage activation, oxygenation and SOFA scores over time; however, it did not lead to differences in the GI-HOPE score.
MeSH
Granulocyte-Macrophage Colony-Stimulating Factor, Macrophage Activation, Macrophages, Granulocytes, Macrophage Colony-Stimulating Factor, Pneumonia, Macrophages, Alveolar, Therapeutics, Respiratory Distress Syndrome, Colony-Stimulating Factors, Host-Directed Therapy