Serum cytokine dysregulation signatures associated with COVID-19 outcomes in high mortality intensive care unit cohorts across pandemic waves and variants

Maaß, Henrike; Ynga-Durand, Mario Alberto; Milosevic, Marko; Krstanović, Fran; Matešić, Marina Pribanić; Žuža, Iva; Jonjić, Stipan; Brizic, Ilija; Šustić, Alan; Bloos, Frank; Protić, Alen; Čičin-Šain, Luka

doi:10.1038/s41598-024-64384-y

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Serum cytokine dysregulation signatures associated with COVID-19 outcomes in high mortality intensive care unit cohorts across pandemic waves and variants

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Author(s): Henrike Maaß ¹ ^, ² , Mario Ynga-Durand ¹ ^, ² , Marko Milošević ³ , Fran Krstanović ⁴ , Marina Pribanić Matešić ⁴ , Iva Žuža ⁵ , Stipan Jonjić ⁴ , Ilija Brizić ⁴ , Alan Šustić ³ ^, ⁶ , Frank Bloos ⁷ , SepNet Critical Care Trials Group, Alen Protić ³ , Luka Čičin-Šain ¹ ^, ² ^, ⁸ ^,

Publication date (Electronic): 13 June 2024

Journal: Scientific Reports

Publisher: Nature Publishing Group UK

Keywords: COVID-19, SARS-CoV-2, Cytokines, Biomarker, Variant of concern, Mortality, SARS-CoV-2, Infectious diseases, Biomarkers, Outcomes research

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Abstract

The aim of this study was to characterize the systemic cytokine signature of critically ill COVID-19 patients in a high mortality setting aiming to identify biomarkers of severity, and to explore their associations with viral loads and clinical characteristics. We studied two COVID-19 critically ill patient cohorts from a referral centre located in Central Europe. The cohorts were recruited during the pre-alpha/alpha (November 2020 to April 2021) and delta (end of 2021) period respectively. We determined both the serum and bronchoalveolar SARS-CoV-2 viral load and identified the variant of concern (VoC) involved. Using a cytokine multiplex assay, we quantified systemic cytokine concentrations and analyzed their relationship with clinical findings, routine laboratory workup and pulmonary function data obtained during the ICU stay. Patients who did not survive had a significantly higher systemic and pulmonary viral load. Patients infected with the pre-alpha VoC showed a significantly lower viral load in comparison to those infected with the alpha- and delta-variants. Levels of systemic CTACK, M-CSF and IL-18 were significantly higher in non-survivors in comparison to survivors. CTACK correlated directly with APACHE II scores. We observed differences in lung compliance and the association between cytokine levels and pulmonary function, dependent on the VoC identified. An intra-cytokine analysis revealed a loss of correlation in the non-survival group in comparison to survivors in both cohorts. Critically ill COVID-19 patients exhibited a distinct systemic cytokine profile based on their survival outcomes. CTACK, M-CSF and IL-18 were identified as mortality-associated analytes independently of the VoC involved. The Intra-cytokine correlation analysis suggested the potential role of a dysregulated systemic network of inflammatory mediators in severe COVID-19 mortality.

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The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min). The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.

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Author and article information

Contributors

Luka Čičin-Šain: Luka.Cicin-Sain@helmholtz-hzi.de

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 13 June 2024

Publication date PMC-release: 13 June 2024

Publication date Collection: 2024

Volume: 14

Electronic Location Identifier: 13605

Affiliations

[1 ]GRID grid.7490.a, ISNI 0000 0001 2238 295X, Department of Viral Immunology, , Helmholtz Center for Infection Research, ; Braunschweig, Germany

[2 ]Centre for Individualized Infection Medicine (CiiM), a joint venture of Helmholtz Centre for Infection Research and Hannover Medical School, ( https://ror.org/04s99xz91) Hannover, Germany

[3 ]Department of Anesthesiology, Faculty of Medicine, Reanimation, Intensive Care and Emergency Medicine, University of Rijeka, ( https://ror.org/05r8dqr10) Rijeka, Croatia

[4 ]Faculty of Medicine, Center for Proteomics, University of Rijeka, ( https://ror.org/05r8dqr10) Rijeka, Croatia

[5 ]GRID grid.412210.4, ISNI 0000 0004 0397 736X, Department of Radiology, , Clinical Hospital Centre Rijeka, ; Rijeka, Croatia

[6 ]Department of Clinical Medical Science II, Faculty of Health Studies, University of Rijeka, ( https://ror.org/05r8dqr10) Rijeka, Croatia

[7 ]Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, ( https://ror.org/035rzkx15) Jena, Germany

[8 ]German Centre for Infection Research (DZIF), Partner Site Hannover/Braunschweig, ( https://ror.org/028s4q594) Braunschweig, Germany

[9 ]Department of Surgical Intensive Care Medicine and Intermediate Care, University Hospital RWTH Aachen, ( https://ror.org/04xfq0f34) Aachen, Germany

[10 ]Department of Anesthesiology and Surgical Intensive Care Medicine, University Hospital Augsburg, ( https://ror.org/03b0k9c14) Augsburg, Germany

[11 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Division of Operative Intensive Care Medicine, Department of Anesthesiology, , Charité Berlin, ; Berlin, Germany

[12 ]Department of Cardiology and Intensive Care Medicine, Vivantes Hospital Neukölln, Berlin, Germany

[13 ]Department of Anesthesiology and Intensive Care Medicine, Division of Intensive Care Medicine, University Hospital Bonn, ( https://ror.org/01xnwqx93) Bonn, Germany

[14 ]Department of Anesthesiology and Intensive Care Medicine, University Hospital Carl Gustav Carus, ( https://ror.org/04za5zm41) Dresden, Germany

[15 ]GRID grid.7708.8, ISNI 0000 0000 9428 7911, Department of General Surgery, , University Hospital Freiburg, ; Freiburg, Germany

[16 ]GRID grid.7450.6, ISNI 0000 0001 2364 4210, Department of Anesthesiology, University Medical Center, , Georg-August-University Göttingen, ; Göttingen, Germany

[17 ]GRID grid.412469.c, ISNI 0000 0000 9116 8976, Depatment of Anesthesiology and Intensive Care Medicine, , University Hospital Greifswald, ; Greifswald, Germany

[18 ]Department of Intensive Care Medicine, University Hospital Hamburg-Eppendorf, ( https://ror.org/03wjwyj98) Hamburg, Germany

[19 ]Department of Pneumology and Infectiology, University Hospital Hannover, ( https://ror.org/05qc7pm63) Hannover, Germany

[20 ]Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, ( https://ror.org/035rzkx15) Jena, Germany

[21 ]Institute of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, ( https://ror.org/035rzkx15) Jena, Germany

[22 ]Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein – Campus Kiel, ( https://ror.org/01tvm6f46) Kiel, Germany

[23 ]Center for Clinical Studies, University Lepizig, ( https://ror.org/03s7gtk40) Leipzig, Germany

[24 ]GRID grid.411095.8, ISNI 0000 0004 0477 2585, Department of Anesthesiology, , University Hospital Munich, ; Munich, Germany

[25 ]Department of Internal Medicine, Division Cardiology, Hospital Nuremberg, ( https://ror.org/010qwhr53) Nuremberg, Germany

[26 ]GRID grid.411544.1, ISNI 0000 0001 0196 8249, Department of Internal Medicine, , University Hospital Tübingen, ; Tübingen, Germany

[27 ]Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, ( https://ror.org/03pvr2g57) Würzburg, Germany

Article

Publisher ID: 64384

DOI: 10.1038/s41598-024-64384-y

PMC ID: 11176334

PubMed ID: 38871772

SO-VID: 7905f53a-c81a-4a5e-ae3b-2a66ab3ac5b2

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 10 October 2023

Date accepted : 7 June 2024

Funding

Funded by: RESIST Excellence cluster

Award ID: EXC 2155, project B6

Award Recipient : Henrike Maaß Konrad Reinhart

Funded by: Croatian Science Foundation

Award ID: IP-CORONA-04-2073

Award Recipient : Ilija Brizić

Funded by: Helmholtz Association’s Initiative and Networking Fund

Award ID: KA1-Co-02 “COVIPA”

Award Recipient : Konrad Reinhart

Funded by: Helmholtz Association EU partnering grant

Award ID: PIE-0008

Award Recipient : Konrad Reinhart

Funded by: Helmholtz-Zentrum für Infektionsforschung GmbH (HZI) (4214)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

Custom metadata

ScienceOpen disciplines: Uncategorized

Keywords: covid-19,sars-cov-2,cytokines,biomarker,variant of concern,mortality,infectious diseases,biomarkers,outcomes research

Data availability:

ScienceOpen disciplines: Uncategorized

Keywords: covid-19, sars-cov-2, cytokines, biomarker, variant of concern, mortality, infectious diseases, biomarkers, outcomes research

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