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Christian Herr,1 Sebastian Mang,1 Bahareh Mozafari,1 Katharina Guenther,1 Thimoteus Speer,2 Martina Seibert,1 Sanjay Kumar Srikakulam,1 Christoph Beisswenger,1 Felix Ritzmann,1 Andreas Keller,3 Rolf Mueller,4 Sigrun Smola,5 Dominic Eisinger,6 Michael Zemlin,7 Guy Danziger,1 Thomas Volk,8 Sabrina Hoersch,8 Marcin Krawczyk,9 Frank Lammert,9 Thomas Adams,9 Gudrun Wagenpfeil,10 Michael Kindermann,11 Constantin Marcu,11 Zuhair Wolf Dietrich Ataya,12 Marc Mittag,13 Konrad Schwarzkopf,13 Florian Custodis,13 Daniel Grandt,13 Harald Schaefer,14 Kai Eltges,14 Philipp M Lepper,1 Robert Bals1 On behalf of the CORSAAR Study Group1Department of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, 66421, Germany; 2Department of Internal Medicine IV - Nephrology and Hypertension & Translational Cardio-Renal Medicine, Saarland University, Homburg, 66421, Germany; 3Clinical Bioinformatics, Saarland University, Homburg, 66421, Germany; 4Helmholtz-Institute for Pharmaceutical Science Saarland, Saarbrücken, 66123, Germany; 5Institute for Virology, Saarland University, Homburg, 66421, Germany; 6Myriad RBM Inc., Austin, TX, 78759, USA; 7Department of General Pediatrics and Neonatology, Saarland University, Homburg, 66421, Germany; 8Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, Saarland University, Homburg, 66421, Germany; 9Department of Internal Medicine II - Gastroenterology, Saarland University, Homburg, 66421, Germany; 10Institute for Medical Biometry, Epidemiology and Medical Informatics, Saarland University, Homburg, 66421, Germany; 11Department of Internal Medicine, Cardiology and Intensive Care Medicine, Caritas Hospital St. Theresia Saarbrücken, Saarbrücken, 66113, Germany; 12Department of Gastroenterology, Internal and Intensive Care Medicine, Caritas Hospital St. Josef Saarbrücken, Saarbrücken, 66125, Germany; 13Department of Anesthesiology, Gastroenterology and Intensive Care Medicine, Saarbrücken Hospital, Saarbrücken, 66119, Germany; 14Department of Internal Medicine and Pulmonology, SHG-Hospital Völklingen, Saarbrücken, 66333, GermanyCorrespondence: Robert BalsDepartment of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, Homburg, 66421, GermanyTel +49 6841 16 15051Email robert.bals@uks.euBackground: COVID-19 comprises several severity stages ranging from oligosymptomatic disease to multi-organ failure and fatal outcomes. The mechanisms why COVID-19 is a mild disease in some patients and progresses to a severe multi-organ and often fatal disease with respiratory failure are not known. Biomarkers that predict the course of disease are urgently needed. The aim of this study was to evaluate a large spectrum of established laboratory measurements.Patients and Methods: Patients from the prospective PULMPOHOM and CORSAAR studies were recruited and comprised 35 patients with COVID-19, 23 with conventional pneumonia, and 28 control patients undergoing elective non-pulmonary surgery. Venous blood was used to measure the serum concentrations of 79 proteins by Luminex multiplex immunoassay technology. Distribution of biomarkers between groups and association with disease severity and outcomes were analyzed.Results: The biomarker profiles between the three groups differed significantly with elevation of specific proteins specific for the respective conditions. Several biomarkers correlated significantly with disease severity and death. Uniform manifold approximation and projection (UMAP) analysis revealed a significant separation of the three disease groups and separated between survivors and deceased patients. Different models were developed to predict mortality based on the baseline measurements of several protein markers. A score combining IL-1ra, IL-8, IL-10, MCP-1, SCF and CA-9 was associated with significantly higher mortality (AUC 0.929).Discussion: Several newly identified blood markers were significantly increased in patients with severe COVID-19 (AAT, EN-RAGE, myoglobin, SAP, TIMP-1, vWF, decorin) or in patients that died (IL-1ra, IL-8, IL-10, MCP-1, SCF, CA-9). The use of established assay technologies allows for rapid translation into clinical practice.Keywords: biomarker, inflammation, SARS-CoV2

Abstract Background Periostin (POSTN) is a secreted extracellular matrix protein of poorly defined function that has been related to bone and heart development as well as to cancer. In human and mouse, it is known to undergo alternative splicing in its C-terminal region, which is devoid of known protein domains. Differential expression of periostin, sometimes of specific splicing isoforms, is observed in a broad range of human cancers, including breast, pancreatic, and colon cancer. Here, we combine genomic and transcriptomic sequence data from vertebrate organisms to study the evolution of periostin and particularly of its C-terminal region. Results We found that the C-terminal part of periostin is markedly more variable among vertebrates than the rest of periostin in terms of exon count, length, and splicing pattern, which we interpret as a consequence of neofunctionalization after the split between periostin and its paralog transforming growth factor, beta-induced (TGFBI). We also defined periostin's sequential 13-amino acid repeat units - well conserved in teleost fish, but more obscure in higher vertebrates - whose secondary structure is predicted to be consecutive beta strands. We suggest that these beta strands may mediate binding interactions with other proteins through an extended beta-zipper in a manner similar to the way repeat units in bacterial cell wall proteins have been reported to bind human fibronectin. Conclusions Our results, obtained with the help of the increasingly large collection of complete vertebrate genomes, document the evolutionary plasticity of periostin's C-terminal region, and for the first time suggest a basis for its functional role.