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

BackgroundThe 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. MethodsIn 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. FindingsThe entry WHO scores were 1-3, 4-5 and 6 in 445 (44{middle dot}0%), 529 (52{middle dot}3%), and 38 (3{middle dot}8%) patients, of whom 119 died and 271 progressed. The standardised odds ratios associated with COV50 for death were 2{middle dot}44 (95% CI, 2{middle dot}05-2{middle dot}92) unadjusted and 1{middle dot}67 (1{middle dot}34-2{middle dot}07) if adjusted for sex, age, body mass index, comorbidities and baseline WHO score, and 1{middle dot}79 (1{middle dot}60-2{middle dot}01) and 1{middle dot}63 (1{middle dot}40-1{middle dot}90), respectively, for disease progression (p<0{middle dot}0001 for all). The predictive accuracy of optimised COV50 thresholds were 74{middle dot}4% (95% CI, 71{middle dot}6-77{middle dot}1) for mortality (threshold 0{middle dot}47) and 67{middle dot}4% (64{middle dot}1-70{middle dot}3) for disease progression (threshold 0{middle dot}04). On top of covariables and the baseline WHO score, these thresholds improved AUCs from 0{middle dot}835 to 0{middle dot}853 (p=0{middle dot}0331) and from 0{middle dot}697 to 0{middle dot}730 (p=0{middle dot}0008) for death and progression, respectively. Of 196 ambulatory patients, 194 (99{middle dot}0%) did not reach the 0{middle dot}04 threshold. Earlier intervention guided by high-risk COV50 levels should reduce hospital days with cost reductions expressed per 1000 patient-days ranging from M{euro} 1{middle dot}208 (95% percentile interval, 1{middle dot}035-1{middle dot}406) at low risk (COV50 <0{middle dot}04) to M{euro} 4{middle dot}503 (4{middle dot}107-4{middle dot}864) at high risk (COV50 [≥]0{middle dot}04 and age [≥]65 years). InterpretationThe 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{middle dot}04 threshold justifies earlier drug treatment, thereby reducing hospitalisation days and costs. FundingGerman Federal Ministry of Health acting upon a decree from the German Federal Parliament.

A proteomic survival predictor for COVID-19 patients in intensive care

Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Comprehensively capturing the host physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index and APACHE II score were poor predictors of survival. Plasma proteomics instead identified 14 proteins that showed concentration trajectories different between survivors and non-survivors. A proteomic predictor trained on single samples obtained at the first time point at maximum treatment level (i.e. WHO grade 7) and weeks before the outcome, achieved accurate classification of survivors in an exploratory (AUROC 0.81) as well as in the independent validation cohort (AUROC of 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that predictors derived from plasma protein levels have the potential to substantially outperform current prognostic markers in intensive care. Trial registrationGerman Clinical Trials Register DRKS00021688

Suppressive myeloid cells are a hallmark of severe COVID-19

Severe Acute Respiratory Syndrome - Coronavirus-2 (SARS-CoV-2) infection causes Coronavirus Disease 2019 (COVID-19), a mild to moderate respiratory tract infection in the majority of patients. A subset of patients, however, progresses to severe disease and respiratory failure with acute respiratory distress syndrome (ARDS). Severe COVID-19 has been associated with increased neutrophil counts and dysregulated immune responses. The mechanisms of protective immunity in mild forms and the pathogenesis of dysregulated inflammation in severe courses of COVID-19 remain largely unclear. Here, we combined two single-cell RNA-sequencing technologies and single-cell proteomics in whole blood and peripheral blood mononuclear cells (PBMC) to determine changes in immune cell composition and activation in two independent dual-center patient cohorts (n=46+n=54 COVID-19 samples), each with mild and severe cases of COVID-19. We observed a specific increase of HLA-DRhiCD11chi inflammatory monocytes that displayed a strong interferon (IFN)-stimulated gene signature in patients with mild COVID-19, which was absent in severe disease. Instead, we found evidence of emergency myelopoiesis, marked by the occurrence of immunosuppressive pre-neutrophils and immature neutrophils and populations of dysfunctional and suppressive mature neutrophils, as well as suppressive HLA-DRto monocytes in severe COVID-19. Our study provides detailed insights into systemic immune response to SARS-CoV-2 infection and it reveals profound alterations in the peripheral myeloid cell compartment associated with severe courses of COVID-19.