ABSTRACT
Rationale: COVID-19 patients present with a number of clinical symptoms ranging from mild, moderate to severe, while only a subgroup of patients, who requires high-dependency critical care resources, accounts for most of the COVID-19 associated health care expenditure and death. A reliable prognostic tool is therefore required to identify patients at risk of developing severe COVID-19 pneumonia. To address this unmet need, we tested a wide range of potentially important peripheral blood biomarkers in a group of clinically risk-stratified COVID-19 patients in order to identify most relevant candidate biomarker(s) predictive of disease progression. Methods: Patients and healthy controls recruited to this study are summarised in Figure 1. Biomarkers levels were analysed using ANOVA across the severity groups. Spearman-correlation coefficients against pairs of average levels from each biomarker within severity-group and healthy controls were assembled into a 76x76 matrix and agglomerative hierarchical clustering was applied to generate the final heatmaps. Linear-discriminant analysis (LDA) was carried out on a reduced optimised set of biomarkers to explore the boundaries between the clinical severity groups.Results: Degree of lymphopaenia, neutrophil levels, TNF-α, INR-levels, and pro-inflammatory cytokines;IL6, IL8, CXCL9 and D-dimers were significantly increased in COVD-19 patients compared to healthy controls (p<0.05, 95% C.I.). C3a and C5 was significantly elevated in all categories of severity compared to healthy controls (p<0.05), C5a levels were significantly different between “moderate” and “severe” categories (p<0.01). sC5b-9 was significantly elevated in the “moderate” and “severe” category of patients compared to healthy controls (p<0.001).Heatmap analysis demonstrated distinct visual differences of biomarker profiles between the clinical severity groups. LDA on the deteriorators, non-deteriorators and healthy volunteers as a combined function of the predictor variables: C3, eosinophil-counts, granulocyte colony-stimulating factor (G-CSF), fractalkine, IL10, IL27, LTB4, lymphocyte count, MIG/CXCL9, M-CSF, platelet count and sC5b-9 showed clear separation between the groups based on biomarker/blood-count levels.Conclusions: Diagnostic and clinical assessments followed by robust statistical and machine learning approaches could identify peripheral blood biomarkers for prognostic stratification of patients in COVID-19. Our results would be helpful for clinicians and supports the use of point of care devices that can quantify multiple analytes. (Lui G, et al., Pointof- care detection of cytokines in cytokine storm management and beyond: Significance and challenges. VIEW. 2021;2: 1-20.). Such would allow for more efficient management and resource allocation. 1 (Figure Presented).
ABSTRACT
Background Originally derived from tick-saliva, nomacopan is a first-in-class dual inhibitor of leukotriene B4 (LTB4) and complement C5. Nomacopan (Coversin) is currently in Phase III development for bullous pemphigoid and HSCT-TMA. In this study, we used nomacopan to treat a small cohort of COVID-19 patients on a compassionate basis. We concurrently present data from a study of biomarkers within a larger cohort of COVID-19 patients, where hyperinflammatory pathways due to complement are highlighted. Methods Patients, healthy-controls and sub-groups recruited to this study are summarised in Figure 1. Betweengroup comparisons in demographic, clinical and biomarker levels were carried out using Kruskal-Wallis and rank-Wilcoxon tests. ROX. SpO2Seven patients (six males and one female) in the CORONET study were treated with nomacopan (1st initial subcutaneous-dose: 45mg of nomacopan (t1/2 = 2.5 hrs), + 2 doses;45 mg, 12-hourly. Subsequently, patients were administered 45mg, od for 12 days. Antibiotic prophylaxis was co-administered. Results ROX indices for patients at enrolment within the CASCADE and CORONET studies were lower than that for normal-healthy individuals, with SpO2 <93%, admitted to ICU or COVID-19 Unit with suspected COVID-19 pneumonia and not on invasive mechanical ventilation on recruitment. Average values for SOFA and NEWS scores were significantly different (p<0.05) between the clinical severities. Values for SOFA and NEWS score were not available for the CORONET study patients.CH50, sC5b-9, C5, C5a, C3, and C3a levels were elevated significantly in CASCADE patients (p<0.05, C.I. 95%).Of the seven patients in the CORONET study, six survived, one (female) died, due to unforeseen circumstances (three days delay to get treatment delivered) from start of symptom onset before starting nomacopan treatment. Conclusion The result of this combined study shows that COVID-19 patients, admitted to hospital with significant symptoms of respiratory difficulty, demonstrated increased circulating levels of components of the complement cascade, potentially linked to lung damage leading to fatality. Interestingly, C5-levels (target of nomacopan) was increased, validating the rationale for anti-C5 treatment of COVID-19 patients. Nomacopan treatment was associated with no noticeable adverse event and without highly elevated as associated with normal C5 and C5a levels. (Figure Presented).