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From Online Data Collection to Identification of Disease Mechanisms: The IL-1ß, IL-6 and TNF-α Cytokine Triad Is Associated With Post-Acute Sequelae of COVID-19 in a Digital Research Cohort

25 Pages Posted: 15 Nov 2021

See all articles by Christoph Schultheiß

Christoph Schultheiß

Martin-Luther-University Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology

Edith Willscher

Martin-Luther-University Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology

Lisa Paschold

Martin-Luther-University Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology

Cornelia Gottschick

Martin Luther University of Halle-Wittenberg - Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI)

Bianca Klee

Martin Luther University of Halle-Wittenberg - Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI)

Saskia Glasauer

Martin Luther University of Halle-Wittenberg - Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI)

Svenja-Sibylla Henkes

Martin Luther University of Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology

Lidia Bosurgi

University of Hamburg - Department of Medicine

Jochen Dutzmann

Martin Luther University of Halle-Wittenberg - Mid-German Heart Center

Daniel G. Sedding

Martin Luther University of Halle-Wittenberg - Mid-German Heart Center

Thomas Frese

Martin Luther University of Halle-Wittenberg - Institute of General Practice and Family Medicine

Matthias Girndt

Martin Luther University of Halle-Wittenberg - Department of Internal Medicine II

Jessica I. Höll

Martin Luther University of Halle-Wittenberg - Pediatric Hematology and Oncology

Michael Gekle

Martin Luther University of Halle-Wittenberg - Julius Bernstein-Institute of Physiology

Rafael Mikolajczyk

Martin Luther University of Halle-Wittenberg - Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI)

Mascha Binder

Martin-Luther-University Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology

More...

Abstract

Background: The COVID-19 pandemic called for a fast conduct of studies to establish vaccines and therapies, but also to identify the natural history and drivers of post-acute sequelae of COVID-19 (PASC). Digital epidemiology may serve this aim by rapidly generating large sample sizes allowing dedicated analyses of biomaterial in a subsample of interest.

Methods: Of 129,733 households in Halle (Saale) invited to the cohort study for digital health research in Germany (DigiHero), 8,077 individuals participated, among these 919 that reported prior positive SARS-CoV-2 testing in their households. These were invited to respond to a PASC-focused questionnaire and to undergo blood sampling for cytokine and autoantibody profiling. Cytokine profiles were validated in a second cohort with early infections and single-cell transcriptomics datasets.

Results: The analysis is based on the first 318 DigiHero participants, 258 thereof on average eight months after mostly mild infection. PASC were reported in 67.8% of cases and consisted predominantly in fatigue, dyspnea and concentration deficit. The recovery from PASC was not associated with post-infection vaccination suggesting that it may not be driven by a cryptic SARS-CoV-2 reservoir. We confirmed the high percentage of individuals with autoantibodies after COVID-19, but found no association with PASC. While our data show that a broad range of cytokines remain deregulated long after infection, IL-1ß, IL-6 and TNF-α represented a triad that was associated with PASC. Blood profiling and single-cell data from early infection indicated that these cytokines are induced in COVID-19 lung pro-inflammatory macrophages creating a feedback loop that may trigger their long-term activation.

Conclusion: We provide evidence for a long-lasting cytokine signature potentially underlying many of the clinical symptoms of PASC that may be driven by macrophage primed during acute infection. This study demonstrates how the combination of digital epidemiology with selective biobanking can rapidly generate hints towards disease mechanisms.

Funding Information: This project was partially funded by the CRC 841 of the German Research Foundation (to MB) as well as by the Medical Faculty of the Martin-Luther-University Halle (Saale).

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: The study was approved by the institutional review board (approval numbers 2020-076) and conducted in accordance with the ethical principles stated by the Declaration of Helsinki. Informed written consent was obtained from all participants or legal representatives.

Keywords: SARS-CoV-2, COVID-19, post-acute sequelae of COVID-19, PASC, long-COVID, DigiHero

Suggested Citation

Schultheiß, Christoph and Willscher, Edith and Paschold, Lisa and Gottschick, Cornelia and Klee, Bianca and Glasauer, Saskia and Henkes, Svenja-Sibylla and Bosurgi, Lidia and Dutzmann, Jochen and Sedding, Daniel G. and Frese, Thomas and Girndt, Matthias and Höll, Jessica I. and Gekle, Michael and Mikolajczyk, Rafael and Binder, Mascha, From Online Data Collection to Identification of Disease Mechanisms: The IL-1ß, IL-6 and TNF-α Cytokine Triad Is Associated With Post-Acute Sequelae of COVID-19 in a Digital Research Cohort. Available at SSRN: https://ssrn.com/abstract=3963839 or http://dx.doi.org/10.2139/ssrn.3963839

Christoph Schultheiß

Martin-Luther-University Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology ( email )

Germany

Edith Willscher

Martin-Luther-University Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology ( email )

Germany

Lisa Paschold

Martin-Luther-University Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology ( email )

Germany

Cornelia Gottschick

Martin Luther University of Halle-Wittenberg - Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI) ( email )

Germany

Bianca Klee

Martin Luther University of Halle-Wittenberg - Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI) ( email )

Germany

Saskia Glasauer

Martin Luther University of Halle-Wittenberg - Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI) ( email )

Germany

Svenja-Sibylla Henkes

Martin Luther University of Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology ( email )

Germany

Lidia Bosurgi

University of Hamburg - Department of Medicine ( email )

Hamburg
Germany

Jochen Dutzmann

Martin Luther University of Halle-Wittenberg - Mid-German Heart Center ( email )

Germany

Daniel G. Sedding

Martin Luther University of Halle-Wittenberg - Mid-German Heart Center ( email )

Germany

Thomas Frese

Martin Luther University of Halle-Wittenberg - Institute of General Practice and Family Medicine ( email )

Germany

Matthias Girndt

Martin Luther University of Halle-Wittenberg - Department of Internal Medicine II ( email )

Germany

Jessica I. Höll

Martin Luther University of Halle-Wittenberg - Pediatric Hematology and Oncology ( email )

Germany

Michael Gekle

Martin Luther University of Halle-Wittenberg - Julius Bernstein-Institute of Physiology ( email )

Germany

Rafael Mikolajczyk

Martin Luther University of Halle-Wittenberg - Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI) ( email )

Germany

Mascha Binder (Contact Author)

Martin-Luther-University Halle-Wittenberg - Department of Internal Medicine IV, Oncology/Hematology ( email )

Germany

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