https://doi.org/10.1007/s00392-025-02625-4
1Justus-Liebig-Universität Giessen Medizinische Klinik I, Kardiologie Bad Nauheim, Deutschland; 2Institut für Klinische Epidemiologie und Biometrie NAPKON Epidemiologiekern Würzburg, Deutschland; 3Universitätsklinikum Gießen und Marburg GmbH Medizinische Klinik I - Kardiologie und Angiologie Gießen, Deutschland; 4Justus-Liebig-Universität Giessen Kardiologie und Angiologie Gießen, Deutschland; 5Kerckhoff Klinik GmbH Abteilung für Kardiologie Bad Nauheim, Deutschland
Background: CCN1 (syn. Cyr61) is a secreted matricellular protein and fulfils important functions in angiogenesis, inflammation and fibrosis development. Increased expression of CCN1 was demonstrated in acute lung injury and overexpression of CCN1 in the lung was associated with increased mortality in mice. We previously identified serum CCN1 as a prognostic marker of mortality in patients with acute coronary syndromes and dilated cardiomyopathy.
Purpose: The aim of the present study was to evaluate the prognostic utility of CCN1 for acute respiratory distress syndrome (ARDS) and 30-day mortality in patients with COVID-19 in a multi-biomarker approach.
Methods: Data from the German National Pandemic Cohort Network (NAPKON) Cross-Sectoral Platform (Sektorenübergreifende Plattform, SUEP) was used for this prospective cohort study. The SUEP cohort includes pediatric and adult patients with a PCR-confirmed COVID-19 diagnosis across various clinical severities. This sub-project included adult Covid-19 patients who were in the critical phase at diagnosis and had biosamples available at baseline. Patients with insufficient data such as missing clinical results or missing relevant dates (diagnosis or result), were excluded. The Acute Respiratory Distress Syndrome (ARDS) status was determined using CT data or by recorded diagnosis. CCN1 and reference biomarkers high-sensitivity CRP (hsCRP), high- sensitivity Troponin T (hsTNT) and N-terminal pro-brain natriuretic peptide (NTproBNP) were measured and analyzed for correlations with developing ARDS or death within 30 days of diagnosis. Spearman correlation and biserial correlation were computed.
Results: We identified 250 COVID-19 patients (mean age 60.8 ± 16.1 (SD) years) of whom 243 completed a 30-day follow-up with available biosamples. Of those patients, 113 developed an ARDS and 25 died within 30 days. Significant correlations with mortality were found for all four biomarkers (CCN1, hsCRP, hsTnT and NTproBNP) to a varying degree. The strongest correlations were found for death and hsTnT (Correlation coefficient 0.53, p < 0.001) and for death and NTproBNP (Correlation coefficient 0.52, p < 0.001). CCN1 and hsCRP were also correlated with death, though weaker (CCN1: correlation coefficient 0.18, p = 0.005; hsCRP: correlation coefficient 0.21, p = 0.002). Other relevant findings include the significant correlation between age and death (Correlation coefficient 0.42, p < 0.001), as well as between glomerular filtration rate (GFR) and NTproBNP (Correlation coefficient -0.54, p < 0.001). No significant correlations between the biomarkers and ARDS were detected.
Conclusion: Baseline hsTnT and NTproBNP levels demonstrate strong associations with 30-day mortality in critically ill COVID-19 patients, while CCN1 and hsCRP exhibit moderate associations. These findings support further investigation into these biomarkers' prognostic value through regression models. The lack of significant correlation between the biomarkers and ARDS may be influenced by variability in documentation, potentially leading to misclassification.