ABSTRACT
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.
Subject(s)
COVID-19 , DeathABSTRACT
Background: The Global Burden Disease 2019 report called for innovation in addressing age-related disabilities. The current study aimed at identifying and validating a urinary peptidomic profile (UPP) differentiating healthy from unhealthy ageing in the general population, to test the UPP predictor in patients, and to search for targetable molecular pathways. Methods: In a Flemish population study (n=778; 50·8% women; age, 16·2-82·1 years), 559 participants were examined twice and made up the derivation and internal validation datasets; 219 were examined once and constituted the independent validation dataset. The UPP was assessed by capillary electrophoresis coupled with mass spectrometry. Statistical methods included linear and proportional hazard regression. Pathway exploration rested on the Reactome and KEGG databases. The multidimensional UPP signature reflecting ageing was further validated in patients with diabetes, COVID-19 or chronic kidney disease. Findings: With correction for multiple testing and multivariable adjustment, chronological age (C‑age) was associated with 210 sequenced peptides mainly showing downregulation of collagen fragments. The trained model relating C‑age to UPP, derived by elastic net regression, included 54 peptides from 17 proteins. In the derivation and the internal and independent validation datasets, the trained model explained 76·3%, 54·4% and 65·3% of C‑age. Compared with the derivation data, the UPP-predicted C‑age was greater (p<0·0001) in age-matched patients with diabetes (n=1575), COVID‑19 infection (n=110) or chronic kidney disease (n=202): 50·3 vs 56·9 vs 58·5 vs 62·3 years. In the population, risk carrying biomarkers were associated (p≤0·037) with UPP‑age, independent of C‑age. Over 12·8‑year (median), the incidence of total and cardiovascular mortality and osteoporosis in the population was associated with UPP‑age, independent of C‑age, with hazard ratios per 10‑year higher UPP‑age of 1·54, 1·72 and 1·40, respectively (p≤0.018). The overrepresented proteins were key nodes in collagen and extracellular-matrix (ECM) turnover. Interpretation: Ageing is associated with a specific UPP signature, reflecting fibrosis and ECM remodelling. UPP‑age was associated with risk factors and adverse health outcomes in the population and with accelerated ageing in patients. Innovation in addressing disability should overcome the ontology of diseases and focus on shared disease mechanisms, in particular the bodywide ageing associated fibrosis and ECM remodelling.Funding: European Research Council, Ministry of the Flemish Community, OMRON Healthcare. Declaration of Interest: HM is the co-founder and co-owner of Mosaiques-Diagnostics GmbH, Hannover, Germany, and AL is an employee of Mosaiques Diagnostics. All other authors declare no conflict of interestEthical Approval: The Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) complies with the Helsinki declaration and is registered at the Belgian Data Protection Authority (reference number III 11/1234/13; 22 August 2013). The ethics committee of the University Hospital Leuven, Belgium, approved the secondary use of FLEMENGHO data (national registration number, B32220083510).