IL-6 and cfDNA monitoring throughout COVID-19 hospitalization are accurate markers of its outcomes

Abstract

Background Severe COVID-19 entails a dysregulated immune response, most likely inflammation related to a lack of virus control. A better understanding of immune toxicity, immunosuppression balance, and COVID-19 assessments could help determine whether different clinical presentations are driven by specific types of immune responses. The progression of the immune response and tissular damage could predict outcomes and may help in the management of patients. Methods We collected 201 serum samples from 93 hospitalised patients classified as moderately, severely, and critically ill. We differentiated the viral, early inflammatory, and late inflammatory phases and included 72 patients with 180 samples in separate stages for longitudinal study and 55 controls. We studied selected cytokines, P-selectin, and the tissue damage markers lactate dehydrogenase (LDH) and cell-free DNA (cfDNA). Results TNF-α, IL-6, IL-8, and G-CSF were associated with severity and mortality, but only IL-6 increased since admission in the critical patients and non-survivors, correlating with damage markers. The lack of a significant decrease in IL-6 levels in the critical patients and non-survivors in the early inflammatory phase (a decreased presence in the other patients) suggests that these patients did not achieve viral control on days 10–16. For all patients, lactate dehydrogenase and cfDNA levels increased with severity, and cfDNA levels increased in the non-survivors from the first sample (p = 0.002) to the late inflammatory phase (p = 0.031). In the multivariate study, cfDNA was an independent risk factor for mortality and ICU admission. Conclusions The distinct progression of IL-6 levels in the course of the disease, especially on days 10–16, was a good marker of progression to critical status and mortality and could guide the start of IL-6 blockade. cfDNA was an accurate marker of severity and mortality from admission and throughout COVID-19 progression.

What is the actual relationship between neutrophil extracellular traps and COVID-19 severity? A longitudinal study

“…The strong correlation of the 2 markers considered the more speci c for NETs, MPO-DNA and NE-DNA, in all severity groups and throughout hospitalization, and the very limited correlation of the remaining biomarkers with each other, suggest that MPO-DNA and NE-DNA are the best circulating NETosis markers. Overall, the results of our study suggest, like others (2,12,41,42), that cfDNA is not a marker with high speci city for NETosis, because it is also released by various hematopoietic cells and from a wide range of tissues after cell destruction, as has been demonstrated in COVID-19 (19,32,41). Also, cfDNA is a DAMP, capable of amplifying the in ammatory response (43,44) via toll-like receptor 9 (TLR-9) (44).…”

“…Our results contradict in some ways some of the other previous results. However, in our previous study with the same samples, AUCs for other markers well known for their association with outcomes in COVID-19, such as IL-6, were validated (19). It seems clear that, with our current limitations in accurately measuring NETs by circulating markers, it is di cult to reach de nitive conclusions about the proper role of NETs in the pathogenesis of COVID-19.…”

“…After having demonstrated the usefulness of cfDNA as a prognostic marker in patients hospitalised for COVID-19 (19), we aimed to check whether these elevated gures were related to NETs, studying the most speci c NET markers longitudinally and throughout the hospitalization of our patient group.…”

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

“…Elevated levels of cf nDNA or mtDNA have been detected in plasma of HIV-1-infected patients ( 87 – 91 ) and of SARS-CoV-2-infected patients ( 19 , 20 , 42 – 44 , 47 , 49 , 52 – 56 , 119 ), as well as in the supernatant of SARS-CoV—infected human airway epithelial cells ( 13 , 18 ).…”

Clinical Characteristics of Severe COVID-19 Patients During Omicron Epidemic and a Nomogram Model Integrating Cell-Free DNA for Predicting Mortality: A Retrospective Analysis

“… 12 cfDNA is only found in trace amounts and has a short half-life in healthy individuals. 13 , 14 Pathological conditions can cause tissue damage and cell necrosis, leading to significantly higher circulating concentrations of cfDNA. CfDNA is an extremely sensitive biomarker for tissue damage.…”