The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19, 2022, Schultheiß et al

Highlights

• We report a post-COVID-19 digital epidemiology study with biomarker analysis (n = 651)
• PASC persists in 60% of participants up to 24 months after mild COVID-19
• PASC is associated with high IL-1β, IL-6, and TNF levels but not autoantibodies
• Overactivated monocytes/macrophages are likely the source of cytokine production

Summary
Post-acute sequelae of COVID-19 (PASC) is emerging as global problem with unknown molecular drivers. Using a digital epidemiology approach, we recruited 8,077 individuals to the cohort study for digital health research in Germany (DigiHero) to respond to a basic questionnaire followed by a PASC-focused survey and blood sampling. We report the first 318 participants, the majority thereof after mild infections. Of those, 67.8% report PASC, predominantly consisting of fatigue, dyspnea, and concentration deficit, which persists in 60% over the mean 8-month follow-up period and resolves independently of post-infection vaccination. PASC is not associated with autoantibodies, but with elevated IL-1β, IL-6, and TNF plasma levels, which we confirm in a validation cohort with 333 additional participants and a longer time from infection of 10 months. Blood profiling and single-cell data from early infection suggest the induction of these cytokines in COVID-19 lung pro-inflammatory macrophages creating a self-sustaining feedback loop.

Open access, https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(22)00195-1