DAMPening Mortality in COVID-19
Authors: Nordin M.J. Hanssen, Bart Spaetgens, Prabhakara R. Nagareddy, Andrew J. Murphy
Journal: Circulation (2021)

With subsequent waves of the coronavirus disease 2019 (COVID-19) pandemic driving ever-climbing mortality, we are currently using dexamethasone as one of the few beneficial treatments for patients with COVID-19 who require oxygen supplementation, providing proof of principle that a dysregulated inflammatory response underlies poor outcomes in COVID-19.Therefore, optimization of the anti-inflammatory approach is likely to save lives.Although great excitement has surrounded the announcement of the potential effectiveness of several vaccines, not much is known yet about the durability of their efficacy, and several logistical issues surrounding mass vaccination efforts have been raised.Therefore, studies into the pathophysiology of the dysregulated immune response that drives COVID-19, and formal testing of already available anti-inflammatory agents, is still warranted to drive down COVID-19-associated mortality.Recent studies have identified a dysregulated myeloid cell compartment as a key characteristic of severe COVID-19 and in their recent publication in Cell, Silvin et al reveal that excess production of damage-associated molecular patterns, commonly abbreviated as "DAMPs"-at least in part-drives this association.In a meticulous study using state of the art flow cytometry and single-cell sequencing, they showed that elevated neutrophil-derived calprotectin (S100A8/A9 [(S100 calcium-binding protein A8 and A9]) levels are linked to immature neutrophils and nonclassical monocytes, which discriminate mild from severe COVID-19, directly implicating the S100A8/A9-driven expansion of myeloid cells in poor outcomes in COVID-19.S100A8/A9 may therefore be a key agent, leading to a potent activation of NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) through interaction with the RAGE (receptor for advanced glycation end products) and TLR4 (toll-like receptor 4), and expansion of inflammatory monocytes, neutrophils, and platelets that, in turn, wreak havoc on the diseased lung tissue and contribute to the hypercoagulable state that contributes to COVID-19 mortality (Figure). 1e hypothesize that these findings also explain why individuals with diabetes, obesity, and cardiovascular disease are at such high risk of poor outcome from COVID-19, and that these findings have several potential implications for clinical practice.We recently found that both chronic and intermittent hyperglycemia lead to increased production of inflammatory monocytes and neutrophils through enhanced S100A8/A9 signaling on RAGE, in a NF-κB-dependent pathway. 2 We hypothesize that dexamethasone use may further elevate S100A8/A9 levels (Figure ), as dexamethasone potently increases circulating neutrophil levels by "softening" them and releasing them into the circulation through rearrangement of the cytoskeleton. 3This is an urgent issue as there currently exists no clear consensus on the effect of dexamethasone on S100A8/A9 levels.We suggest that dexamethasone may be able to reduce at least some of the excess risk of poor outcome in COVID-19 infection in diabetes and that its beneficial effects are hampered DAMPening Mortality in COVID-19