GM-CSF Pinpointed as Possible Therapeutic Target for COVID-19

GM-CSF Pinpointed as Possible Therapeutic Target for COVID-19

2021-03-24

NEW YORK (Reuters Health) – Granulocyte-macrophage colony-stimulating factor (GM-CSF) seems to play a key role in severe COVID-19 inflammation, supporting therapeutic targeting of this cytokine, researchers suggest.

To investigate the pathways that drive COVID-19 severity and distinguish it from other viral lung diseases, Dr. Peter Openshaw of Imperial College, London, UK and colleagues analyzed plasma samples from 471 hospitalized patients and 39 outpatients with mild disease.

As reported in Science Immunology, they stratified patients into five groups based on peak illness severity, according to the World Health Organization COVID-19 ordinal scale: (1) no oxygen requirement (severity 3); (2) requiring oxygen by face mask or nasal prongs (severity 4); (3) high-flow nasal cannulae oxygen or non-invasive ventilation (severity 5); (4) invasive mechanical ventilation (severity 6/7); and (5) fatal COVID-19 (severity 8).

Among the findings:

– Routine clinical data did not completely distinguish COVID-19 severities.

– A broad inflammatory response scaled with COVID-19 severity; progressive elevation of numerous inflammatory cytokines and chemokines – including IL-6, CXCL10, and GM-CSF – were associated with severity and accompanied by raised markers of endothelial injury and thrombosis.

– As per other reports, IL-6 was significantly elevated in most hospitalized groups relative to controls, with a stepwise increase in levels with escalating severity; IL-6 levels in groups with severities 6/7 and 8 were significantly elevated above all other groups, and GM-CSF was similarly elevated in all hospitalized groups relative to controls.

– Principal component and network analyses showed central roles for IL-6 and GM-CSF in COVID-19 pathogenesis.

– GM-CSF and IL-1 alpha distinguished fatal COVID-19 from fatal influenza, with GM-CSF especially distinguishing COVID-19 patients from cases of influenza; IL-6 was equally elevated in both conditions, whereas GM-CSF was prominent only in COVID-19.

“Our findings support therapeutic targeting of GM-CSF, as previously suggested on theoretical grounds,” the authors conclude.

Dr. Jess Mandel, Chief, Division of Pulmonary, Critical Care, and Sleep Medicine, and Vice-Chair for Education, Department of Internal Medicine at UC San Diego School of Medicine, commented by email to Reuters Health. “The results of this study are interesting, but need to be considered in context. This manuscript is ‘hypothesis-generating,’ rather than conclusive.”

“The immune system is fantastically complicated, and most interventions that have focused on targeting individual inflammatory molecules in severe infectious illnesses have failed or had limited success,” he noted. “There is also a human disease state called pulmonary alveolar proteinases that is associated with low circulating levels of GM-CSF, which suggests that a more sophisticated approach than simply targeting GM-CSF signaling would be required in order to transform the author’s central observation into a therapeutic strategy.”

Rheumatologist Dr. Bibi Ayesha, Director, Vasculitis Clinic, and Lead, COVID-19 Cytokine Storm Task Force at Montefiore Health System in New York City also commented by email. “The findings of this study are not generalizable, as the sample size was small. There was no detailed description of the patient population and their baseline demographic characteristics.”

“Any virus infection leads to a cytokine response,” she told Reuters Health. “However, in COVID-19, there is a subset of patients who rapidly progress to dysregulated cytokine release, leading to COVID-19 cytokine storm syndrome.”

“Few studies have shown that therapy targeting these cytokines with anti-interleukin-1 (anti IL-1) and anti-interluekin-6 (anti-IL 6) reduces the systemic inflammatory response, which can prevent rapid progression of cytokine-mediated diffuse alveolar damage,” she said.

“There is extremely limited literature on the safety and efficacy of biologic immunosuppressive therapy in COVID-19 patients,” she added. “To date, there are no formal guidelines as to when to initiate immunosuppressive therapy in COVID-19 patients (and) further studies are needed to identify the specific timeframe.”

Corresponding authors Drs. Openshaw, Semple and Baillie did not provide a comment.

SOURCE: https://bit.ly/3cdESCI Science Immunology, online March 10, 2021.

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