Distinct patterns of blood cytokines beyond a cytokine storm predict mortality in COVID-19

Distinct patterns of blood cytokines beyond a cytokine storm predict mortality in COVID-19. Herr, C., Mang, S., Mozafari, B., Günther, K., Speer, T., Seibert, M., Srikakulam, S. K., Beisswenger, C., Ritzmann, F., Keller, A., Müller, R., Smola, S., Eisinger, D., Zemlin, M., Danziger, G., Volk, T., Hörsch, S., Krawczyk, M., Lammert, F., Adams, T., Wagenpfeil, G., Kindermann, M., Marcu, C., Ataya, Z. W. D., Mittag, M., Schwarzkopf, K., Custodis, F., Grandt, D., Schäfer, H., Eltges, K., Lepper, P. M., Bals, R., & study group , C. medRxiv, Cold Spring Harbor Laboratory Press, 2021.

Paper doi abstract bibtex

Background 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.Findings 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.Interpretation Several newly identified blood markers were increased in patients with severe COVID-19 (AAT, EN-RAGE, ICAM-1, myoglobin, SAP, TIMP-1, vWF, decorin, HGF, MMP7, PECAM-1) or in patients that died (FRTN, SCF, TIMP-1, CA-9, CEA, decorin, HGF). The use of established assay technologies allows for rapid translation into clinical practice.Funding No role of the funding source.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe funders of the study had no role in study design, data collection, data interpretation, or writing of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. This work was supported by grants of the Rolf M. Schwiete Stiftung (2020-013), the Saarland University, and The State of Saarland. Protein biomarker assays have been performed in collaboration with Myriad RBM.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The studies have been approved by the ethics committee of the Aerztekammer des Saarlandes, and all patients or their legal representatives gave their informed consent.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data concerning this manuscript is available within the manuscript or its supplement.

@article {Herr2021.05.04.21256497,
	author = {Herr, Christian and Mang, Sebastian and Mozafari, Bahareh and G{\"u}nther, Katharina and Speer, Thimoteus and Seibert, Martina and Srikakulam, Sanjay Kumar and Beisswenger, Christoph and Ritzmann, Felix and Keller, Andreas and M{\"u}ller, Rolf and Smola, Sigrun and Eisinger, Dominic and Zemlin, Michael and Danziger, Guy and Volk, Thomas and H{\"o}rsch, Sabrina and Krawczyk, Marcin and Lammert, Frank and Adams, Thomas and Wagenpfeil, Gudrun and Kindermann, Michael and Marcu, Constantin and Ataya, Zuhair Wolf Dietrich and Mittag, Marc and Schwarzkopf, Konrad and Custodis, Florian and Grandt, Daniel and Sch{\"a}fer, Harald and Eltges, Kai and Lepper, Philipp M. and Bals, Robert and CORSAAR study group},
	title = {Distinct patterns of blood cytokines beyond a cytokine storm predict mortality in COVID-19},
	elocation-id = {2021.05.04.21256497},
	year = {2021},
	doi = {10.1101/2021.05.04.21256497},
	publisher = {Cold Spring Harbor Laboratory Press},
	abstract = {Background 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.Findings 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.Interpretation Several newly identified blood markers were increased in patients with severe COVID-19 (AAT, EN-RAGE, ICAM-1, myoglobin, SAP, TIMP-1, vWF, decorin, HGF, MMP7, PECAM-1) or in patients that died (FRTN, SCF, TIMP-1, CA-9, CEA, decorin, HGF). The use of established assay technologies allows for rapid translation into clinical practice.Funding No role of the funding source.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe funders of the study had no role in study design, data collection, data interpretation, or writing of the report. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. This work was supported by grants of the Rolf M. Schwiete Stiftung (2020-013), the Saarland University, and The State of Saarland. Protein biomarker assays have been performed in collaboration with Myriad RBM.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The studies have been approved by the ethics committee of the Aerztekammer des Saarlandes, and all patients or their legal representatives gave their informed consent.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data concerning this manuscript is available within the manuscript or its supplement.},
	URL = {https://www.medrxiv.org/content/early/2021/05/04/2021.05.04.21256497},
	eprint = {https://www.medrxiv.org/content/early/2021/05/04/2021.05.04.21256497.full.pdf},
	journal = {medRxiv}
}

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