Predictive performance and clinical application of COV50, a urinary proteomic biomarker in early COVID-19 infection: a cohort study (preprint)

Background The SARS CoV-2 pandemic remains a worldwide challenge. The CRIT Cov U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression. Following the interim analysis demanded by the German government, the full dataset was analysed to consolidate findings and propose clinical applications. Methods In eight European countries, 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8 point WHO scale. Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling. Statistical methods included logistic regression, receiver operating curve analysis with comparison of the area under curve (AUC) between nested models. Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalistion costs standardised across countries. Findings The entry WHO scores were 1-3, 4-5 and 6 in 445 (44,0%), 529 (52,3%), and 38 (3,8%) patients, of whom 119 died and 271 progressed. The standardised odds ratios associated with COV50 for death were 2,44 (95% CI, 2,05-2,92) unadjusted and 1,67 (1,34-2,07) if adjusted for sex, age, body mass index, comorbidities and baseline WHO score, and 1,79 (1,60-2,01) and 1,63 (1,40-1,90), respectively, for disease progression (p<0,0001 for all). The predictive accuracy of optimised COV50 thresholds were 74,4% (95% CI, 71,6-77,1) for mortality (threshold 0,47) and 67,4% (64,1-70,3) for disease progression (threshold 0,04). On top of covariables and the baseline WHO score, these thresholds improved AUCs from 0,835 to 0,853 (p=0,0331) and from 0,697 to 0,730 (p=0,0008) for death and progression, respectively. Of 196 ambulatory patients, 194 (99,0%) did not reach the 0,04 threshold. Earlier intervention guided by high-risk COV50 levels should reduce hospital days with cost reductions expressed per 1000 patient-days ranging from MEuro 1,208 (95% percentile interval, 1,035-1,406) at low risk (COV50 <0,04) to MEuro 4,503 (4,107-4,864) at high risk (COV50 above 0,04 and age above 65 years). Interpretation The urinary proteomic COV50 marker is accurate in predicting adverse COVID-19 outcomes. Even in mild-to-moderate PCR-confirmed infections (WHO scores 1-5), the 0,04 threshold justifies earlier drug treatment, thereby reducing hospitalisation days and costs.

Clinical Relevance of Elevated Soluble ST2, HSP27 and 20S Proteasome in Patients with COVID-19 (preprint)

Although, severe acute respiratory syndrome coronavirus – 2 (SARS-CoV 2) represents one of the biggest challenges in the world today, the exact immunopathogenic mechanism that leads to severe or critical Coronavirus Disease 2019 (COVID-19) has remained incompletely understood. Several studies have indicated that high systemic plasma levels of inflammatory cytokines result in the so-called “cytokine storm”, with subsequent development of microthrombosis, disseminated intravascular coagulation, and multiorgan-failure. Therefore, we reasoned that elevated inflammatory cytokine might act as prognostic factors. Here, we analyzed 245 serum samples of patients with COVID-19, collected at hospital admission. We assessed the levels of heat shock protein 27 (HSP27), soluble suppressor of tumorigenicity- 2 (sST2), caspase cleaved cytokeratin 18 (cCK18), 20S proteasome, and tumor necrosis factor receptor 1 (TNFR-1) and explored their associations with overall-, 30-, 60-, 90-day- and in-hospital mortality. Moreover, we investigated their association with the risk of ventilation. We demonstrated that increased serum sST2 was uni- and multivariably associated with all endpoints. However, we also identified 20S proteasome as independent prognostic factor for in-hospital mortality. Furthermore, elevated HSP27, sST2, and 20S proteasome levels at hospital admission were univariably associated with higher risk of invasive ventilation. These findings could help to identify high-risk patients early in the course of COVID-19.

Critical COVID-19 represents an endothelial disease with high similarity to kidney disease on the molecular level (preprint)

In patients with critical or mild COVID19 (WHO stages 6-8 [n=53] and stages 1-3 [n=66]), 593 urinary peptides significantly affected by disease severity were identified, reflecting the molecular pathophysiology associated with the course of the infection. The peptide profiles were similar compared with those observed in kidney disease, a prototype of target organ damage with major microvascular involvement, thereby confirming the observation that endothelial damage is a hallmark of COVID19. The clinical corollary is that COVID19 is an indication for anti-oxidative, anti-inflammatory and immunosuppressive treatment modalities protecting the endothelial lining.