Redefining COVID-19 Severity and Prognosis: The Role of Clinical and Immunobiotypes

Abstract

BackgroundMost of the explanatory and prognostic models of COVID-19 lack of a comprehensive assessment of the wide COVID-19 spectrum of abnormalities. The aim of this study was to unveil novel biological features to explain COVID-19 severity and prognosis (death and disease progression).MethodsA predictive model for COVID-19 severity in 121 patients was constructed by ordinal logistic regression calculating odds ratio (OR) with 95% confidence intervals (95% CI) for a set of clinical, immunological, metabolomic, and other biological traits. The accuracy and calibration of the model was tested with the area under the curve (AUC), Somer’s D, and calibration plot. Hazard ratios with 95% CI for adverse outcomes were calculated with a Cox proportional-hazards model.ResultsThe explanatory variables for COVID-19 severity were the body mass index (BMI), hemoglobin, albumin, 3-Hydroxyisovaleric acid, CD8+ effector memory T cells, Th1 cells, low-density granulocytes, monocyte chemoattractant protein-1, plasma TRIM63, and circulating neutrophil extracellular traps. The model showed an outstanding performance with an optimism-adjusted AUC of 0.999, and Somer’s D of 0.999. The predictive variables for adverse outcomes in COVID-19 were severe and critical disease diagnosis, BMI, lactate dehydrogenase, Troponin I, neutrophil/lymphocyte ratio, serum levels of IP-10, malic acid, 3, 4 di-hydroxybutanoic acid, citric acid, myoinositol, and cystine.ConclusionsHerein, we unveil novel immunological and metabolomic features associated with COVID-19 severity and prognosis. Our models encompass the interplay among innate and adaptive immunity, inflammation-induced muscle atrophy and hypoxia as the main drivers of COVID-19 severity.

NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond

“…Importantly, LDG ratios are increased in individuals with COVID-19. The amounts of LDGs are further upregulated in individuals with severe COVID-19 where it is indicative for poor clinical prognoses (23)(24)(25). Furthermore, LDGs are prone to NETosis and NET formation, thereby contributing to COVID-19-related immunothrombosis and organ injury (26).…”

A systematic review on neutrophil extracellular traps and its prognostication role in COVID-19 patients

“…The total number of participants from all included research was 810, with 696 of them diagnosed with COVID-19 (confirmed by RT-PCR test), all of whom were adults. Four of those studies only examined COVID-19 patients [ 30 , 34 , 36 , 37 ]. The most common markers used to determine the level of circulating NETs were MPO-DNA complexes [ 13 , 31 – 33 , 37 ], cfDNA [ 13 , 29 , 30 , 37 ], and histones (either in H3Cit or histone-DNA complexes) [ 13 , 29 – 31 , 37 ].…”

“…The most common markers used to determine the level of circulating NETs were MPO-DNA complexes [ 13 , 31 – 33 , 37 ], cfDNA [ 13 , 29 , 30 , 37 ], and histones (either in H3Cit or histone-DNA complexes) [ 13 , 29 – 31 , 37 ]. The majority of the studies compared the surrogate marker of NET levels between COVID-19 patients and healthy donors, while only four studies contrasted it to the severity spectrum of COVID-19 [ 31 , 32 , 34 , 35 ]. Thromboembolic events [ 29 , 31 – 33 , 37 ] and the need for mechanical ventilation [ 13 , 29 , 32 ] were the most frequently observed criterion for identifying increased disease severity.…”

“…Thromboembolic events [ 29 , 31 – 33 , 37 ] and the need for mechanical ventilation [ 13 , 29 , 32 ] were the most frequently observed criterion for identifying increased disease severity. Eight studies were cohort [ 13 , 29 – 34 , 37 ], meanwhile the remaining publications were cross-sectional [ 35 , 36 ] in design.…”

“…al. (2020) [ 33 ] Greece Cohort (prospective) 35 patients (25 COVID-19 patients and 10 control) Investigate the role of neutrophils in COVID-19 thromboinflammation through complement activation • Significant increase ( p < 0.05) in MPO-DNA complex in COVID-19 patients vs. healthy control was positively correlated with TAT activity • NETs are associated with activation of the TF/thrombin axis in COVID-19 patients, thus potentially contributing to immunothrombosis Torres-Ruiz (2021)a [ 34 ] Mexico Cohort (prospective) 121 patients with COVID-19 Create and validating a compound explanatory model to classify COVID-19 patients according to their disease severity and to predict adverse outcomes • Circulating NETs complexes were higher in severe and critical patients in comparison to mild/moderate subjects Torres-Ruiz, et.al. (2021)b [ 35 ] Mexico Cross-sectional 92 patients (82 with positive RT-PCR, 10 healthy donors) Investigate the production of NETs and their role as inducers of macrophage and autoimmune responses in COVID-19 patients • COVID-19 patients produced a higher level of NETs vs. healthy donors • COVID-19 patients in severe states have a significant deficient degradation of NETs in comparison to mild/moderate COVID-19 ( p = 0.0297) • Patient with COVID-19 (either mild/moderate, severe and critical) all have an increase in NETs-recognizing antibodies, and it is sequential according to disease conditions Wang, et.…”