Combination of WFDC2, CHI3L1, and KRT19 in Plasma Defines a Clinically Useful Molecular Phenotype Associated with Prognosis in Critically Ill COVID-19 Patients

Abstract

Background COVID-19 is now a common disease, but its pathogenesis remains unknown. Blood circulating proteins reflect host defenses against COVID-19. We investigated whether evaluation of longitudinal blood proteomics for COVID-19 and merging with clinical information would allow elucidation of its pathogenesis and develop a useful clinical phenotype. Methods To achieve the first goal (determining key proteins), we derived plasma proteins related to disease severity by using a first discovery cohort. We then assessed the association of the derived proteins with clinical outcome in a second discovery cohort. Finally, the candidates were validated by enzyme-linked immunosorbent assay in a validation cohort to determine key proteins. For the second goal (understanding the associations of the clinical phenotypes with 28-day mortality and clinical outcome), we assessed the associations between clinical phenotypes derived by latent cluster analysis with the key proteins and 28-day mortality and clinical outcome. Results We identified four key proteins (WFDC2, GDF15, CHI3L1, and KRT19) involved in critical pathogenesis from the three different cohorts. These key proteins were related to the function of cell adhesion and not immune response. Considering the multicollinearity, three clinical phenotypes based on WFDC2, CHI3L1, and KRT19 were identified that were associated with mortality and clinical outcome. Conclusion The use of these easily measured key proteins offered new insight into the pathogenesis of COVID-19 and could be useful in a potential clinical application.

New insights into the role of the CHI3L2 protein in invasive ductal breast carcinoma: the CHI3L1 protein has a different role

“…Furthermore, our results show a correlation between the expression of CHI3L1 and Nogo-A in IDC and their involvement in angiogenesis in this cancer subtype [20]. Recent studies also indicate increased levels of CHI3L1 in bronchoalveolar lavage uid and serum of critical COVID-19 patients, suggesting the possible involvement of this protein in the pathogenesis of the disease and its importance as a biomarker [21][22][23].…”

Disrupted epithelial permeability as a predictor of severe COVID‐19 development

“…Another important finding of the present study is to link certain protein biomarkers with disease progression from moderate to severe COVID‐19 and death. CXCL10, 49,50 HGF, 49,51,62,63 EIF4EBP1, 64,65 KRT19, 57,66 ITGB6, 66 CKAP4, 67,68 CLEC7A, 69 LAMP3, 70,71 and TRANCE 49,51 have been demonstrated to be involved in COVID‐19 pathogenesis in previous studies. In addition, coxsackievirus and adenovirus receptor (CXADR) appeared as a novel biomarker of COVID‐19, predicting disease severity and death.…”

“…46 In addition, endothelial barrier leakage may play an important role in local and systemic COVID-19 pathology with elevated levels of several endothelial markers, endotheliitis and is associated with COVID-19 disease severity. 47,48 Concerning inflammation and immune response biomarkers associated with COVID-19 disease severity, a hyper inflammatory response with high levels of CXCL10 and CXCL11, 6,49,50 TRANCE, 49,51 CLEC4C, [52][53][54] and AREG 6,53,[55][56][57] emerged among the strongest predictors of disease severity. In addition, the novel biomarker AXIN1 was strongly associated with increased bacterial DNA levels and disease severity.…”

“…Concerning inflammation and immune response biomarkers associated with COVID‐19 disease severity, a hyper inflammatory response with high levels of CXCL10 and CXCL11, 6,49,50 TRANCE, 49,51 CLEC4C, 52–54 and AREG 6,53,55–57 emerged among the strongest predictors of disease severity. In addition, the novel biomarker AXIN1 was strongly associated with increased bacterial DNA levels and disease severity.…”

Analysis of comprehensive biomolecules in critically ill patients via bioinformatics technologies

“…identified major blood proteins based on a proteomic analysis of plasma from patients with severe COVID‐19 using the PEA method and reported that measurement of three proteins (WFDC2, CHI3L1, and KRT19) could identify the poor prognostic subtype, suggesting that measurement could predict severity of COVID‐19 at an early stage. 15 …”