Biomarkers of cell damage, neutrophil and macrophage activation associated with in-hospital mortality in geriatric COVID-19 patients

Abstract

Background The risk for symptomatic COVID-19 requiring hospitalization is higher in the older population. The course of the disease in hospitalised older patients may show significant variation, from mild to severe illness, ultimately leading to death in the most critical cases. The analysis of circulating biomolecules involved in mechanisms of inflammation, cell damage and innate immunity could lead to identify new biomarkers of COVID-19 severity, aimed to improve the clinical management of subjects at higher risk of severe outcomes. In a cohort of COVID-19 geriatric patients (n= 156) who required hospitalization we analysed, on-admission, a series of circulating biomarkers related to neutrophil activation (neutrophil elastase, LL-37), macrophage activation (sCD163) and cell damage (nuclear cfDNA, mithocondrial cfDNA and nuclear cfDNA integrity). The above reported biomarkers were tested for their association with in-hospital mortality and with clinical, inflammatory and routine hematological parameters. Aim of the study was to unravel prognostic parameters for risk stratification of COVID-19 patients. Results Lower n-cfDNA integrity, higher neutrophil elastase and higher sCD163 levels were significantly associated with an increased risk of in-hospital decease. Median (IQR) values observed in discharged vs. deceased patients were: 0.50 (0.30-0.72) vs. 0.33 (0.22-0.62) for n-cfDNA integrity; 94.0 (47.7-154.0) ng/ml vs. 115.7 (84.2-212.7) ng/ml for neutrophil elastase; 614.0 (370.0-821.0) ng/ml vs. 787.0 (560.0-1304.0) ng/ml for sCD163. The analysis of survival curves in patients stratified for tertiles of each biomarker showed that patients with n-cfDNA integrity < 0.32 or sCD163 in the range 492-811 ng/ml had higher risk of in-hospital decease than, respectively, patients with higher n-cfDNA integrity or lower sCD163. These associations were further confirmed in multivariate models adjusted for age, sex and outcome-related clinical variables. In these models also high levels of neutrophil elastase (>150 ng/ml) appeared to be independent predictor of in-hospital death. An additional analysis of neutrophil elastase in patients stratified for n-cfDNA integrity levels was conducted to better describe the association of the studied parameters with the outcome. Conclusions On the whole, biomarkers of cell-free DNA integrity, neutrophil and macrophage activation might provide a valuable contribution to identify geriatric patients with high risk of COVID-19 in-hospital mortality.

Organ-Dysfunction Markers in Mild-to-Moderate COVID-19 Convalescents

“…Soluble CD163 (sCD163) in plasma comes from the surface of activated monocytes/macrophages after enzymatic shedding by ADAM17/TACE metalloproteinase, and its concentration corresponds to the intensity of the inflammatory response [24]. This marker has already been analyzed in the acute phase of COVID-19, with an increased concentration in patients admitted to intensive care units due to severe disease or these with a fatal outcome [24][25][26]. Increases in sCD163 in the course of COVID-19 has also been confirmed in children.…”

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

“…The DAMP most frequently reported for COVID-19 is lactate dehydrogenase, a central enzyme of anaerobic glycolysis that is present in virtually all cells and that, therefore, reliably indicates cell death when occurring at high concentrations in the extracellular space ( 200 – 202 ). Other DAMPs which have been observed at elevated levels in the blood or plasma of patients with severe COVID-19 comprise high-mobility group box protein (HMGB)1 ( 51 , 110 , 111 , 202 – 206 ), S100 proteins ( 108 , 110 , 202 , 207 – 209 ), plasma hyaluronan ( 210 ), extracellular (e)ATP ( 211 , 212 ), the antimicrobial peptide LL-37 ( 213 , 214 ), histones (e.g ( 215 – 217 ), reviewed in ( 218 , 219 ) and circulating self-DNA, including nDNA ( 13 , 20 , 21 , 42 , 46 , 47 ), mtDNA ( 13 , 18 , 21 , 42 , 43 , 48 , 49 ), NET-associated cfDNA ( 201 , 215 , 220 – 222 ), histone-DNA complexes ( 219 ), and cfDNA of non-specified subcellular origin ( 45 , 48 , 50 – 54 ). As recently reviewed for sepsis ( 72 ), most of these studies reported a positive correlation of the plasma levels of at least some of the beforementioned DAMPs with the degree of disease severity (e.g., mild versus severe cases, COVID-19 patients at ICU admission versus healthy controls, ICU-admitted cases with fatal outcomes versus surviving patients, poor oxygenation status, patients with acute respiratory distress syndrome or with multisystem inflammatory syndrome in children, etc.).…”

“…Even autoantibodies are also being reported from COVID-19 patients ( 143 , 256 , 258 ). The other way round, several of the studies that tested for plasma concentrations of nDNA or mtDNA failed to detect a statistically significant difference between light and severe cases or between deceased and discharged patients ( 21 ). Likewise, I am only aware of a single report that connects adverse effects of the COVID-19 mRNA vaccine to inflammasome-activation ( 352 ).…”

“…Several studies identified DNA-sensing pattern recognition receptors (PRRs) as drivers of IFN I-driven inflammation and massive cell death in severe COVID-19: cyclic GMP-AMP synthase (cGAS), absent in melanoma (AIM)2, nucleotide-binding oligomerization domain (NOD)-like leucine-rich repeat (LRR) and PYRIN domain containing (NLRP)3, receptor for advanced glycation end products (RAGE), and Toll-like receptor (TLR)9 (9,13,14,(17)(18)(19)(20)(21)(22)(23): Upon detecting double stranded (ds)DNA, these PRRs activate the production of antiviral and pro-inflammatory cytokines and chemokines and eventually, cell death, via two principal pathways (reviewed in (24,25)). While cGAS signals via stimulator of interferon genes (STING) to induce predominantly IFN I, TLRs signal via the adaptor protein myeloid differentiation primary response (MyD)88 and the transcription factor NF-kB to activate the expression of IL-1b, IL-6 and IL-18 and of AIM2, NLRP3 and other elements of the inflammasome.…”

Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people

“…Besides the lymphoid response which is protective, the myeloid response (neutrophils and monocytes) is also implicated in disease severity and tissue lesions during COVID-19 [ 18 – 20 ]. Neutrophil and macrophage circulating biomarkers are associated with mortality in older patients [ 21 ].…”