ABSTRACT
Background. Numerous predictive clinical scores with varying discriminatory performance have been developed in the context of the current coronavirus disease 2019 (COVID-19) pandemic. To support clinical application, we test the transferability of the frequently applied 4C mortality score (4C score) to the German prospective Cross-Sectoral Platform (SUEP) of the National Pandemic Cohort Network (NAPKON) compared to the non COVID-19 specific quick sequential organ failure assessment score (qSOFA). Our project aims to externally validate these two scores, stratified for the most prevalent variants of concerns (VOCs) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in Germany. Methods. A total of 685 adults with polymerase chain reaction (PCR)-detected SARS-CoV-2 infection were included from NAPKON-SUEP. Patients were recruited from 11/2020 to 03/2022 at 34 university and non-university hospitals across Germany. Missing values were complemented using multiple imputation. Predictive performance for in-hospital mortality at day of baseline visit was determined by area under the curve (AUC) with 95%-confidence interval (CI) stratified by VOCs of SARS-CoV-2 (alpha, delta, omicron) (Figure 1). Figure 1: Study flow chart with inclusion criteria and methodological workflow. Results. Preliminary results suggest a high predictive performance of the 4C score for in-hospital mortality (Table 1). This applies for the overall cohort (AUC 0.813 (95%CI 0.738-0.888)) as well as the VOC-strata (alpha: AUC 0.859 (95%CI 0.748-0.970);delta: AUC 0.769 (95%CI 0.657-0.882);omicron: AUC 0.866 (95%CI 0.724-1.000)). The overall mortality rates across the defined 4C score risk groups are 0.3% (low), 3.2% (intermediate), 11.6% (high), and 49.5% (very high). The 4C score performs significantly better than the qSOFA (Chi2-test: p=0.001) and the qSOFA does not seem to be a suitable tool in this context. Table 1: Discriminatory performance of the 4C Mortality Score and the qSOFA score within the validation cohort NAPKON-SUEP stratified by the Variant of Concerns of SARS-CoV- 2. Conclusion. Despite its development in the early phase of the pandemic and improved treatment, external validation of the 4C score in NAPKON-SUEP indicates a high predictive performance for in-hospital mortality across all VOCs. However, since the qSOFA was not specifically designed for this predictive issue, it shows low discriminatory performance, as in other validation studies. Any interpretations regarding the omicron stratum are limited due to the sample size.
ABSTRACT
Background: Antiphospholipid antibodies (aPL) are causally involved in the pathogenesis of the antiphospholipid syndrome (APS), but lipid-binding aPL are also frequently found in acute infections. While lipid-binding aPL are considered irrelevant for APS we have shown that they are prothrombotic in vivo and have delineated the underlying signaling pathway. COVID-19 associated coagulopathy has many similarities to severe and catastrophic APS e.g. stroke, venous and pulmonary clots, as well as microvascular thrombosis and aPL have been described in COVID-19. However, their role in COVID-19 is still poorly understood. Aims: In this study, we aimed to elucidate the role of lipid-binding aPL in severe COVID-19. Methods: B cells were analyzed using flow cytometry. aPL were measured by immunoassays including a home-made ELISA for lipidbinding aPL. Cultured cells were stimulated with immunoglobulins isolated from COVID-19 patients. Gene expression was measured by qRT-PCR, cellular procoagulant activity was determined by a clotting assay. In vivo thrombus formation was determined in the flowrestricted inferior vena cava mouse model. Results: We identified a distinct population of circulating B1a cells producing lipid-reactive aPL of the IgG isotype in COVID-19 patients. 43 of 53 COVID-19 patients tested positive for lipid-binding aPL. Positive patients had more often a critical clinical course and a higher mortality. In vitro, COVID-19 aPL induced inflammatory and prothrombotic pathways in monocytes and endothelial cells and rapidly decrypted cell surface tissue factor. These effects were dependent on a recently described signaling pathway involving lysobisphosphatidic acid (LBPA) presented by the endothelial protein C receptor (EPCR) on the cell surface. In vivo, COVID-19 aPL induced thrombus formation by this EPCR-LBPA-dependent signaling pathway. Conclusions: COVID-19 patients develop lipid-binding aPL produced by circulating B1a cells. These aPL are associated with a more severe course and mortality and show prothrombotic and inflammatory properties by targeting the previously delineated aPL autoimmune signaling pathway dependent on EPCR-LBPA.