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

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-1s, 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.