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

Abstract

Post-acute sequelae of COVID-19 (PASC) emerge as a global problem with unknown molecular drivers. In a digital epidemiology approach, we rapidly recruited 8,077 individuals out of 129,733 households in Halle (Saale) to the cohort study for digital health research in Germany (DigiHero). These responded to a basic questionnaire followed by a PASC-focused survey and blood sampling in case of prior positive SARS-CoV-2 testing in their household. The presented analysis is based on the first 318 DigiHero participants, the majority thereof after mild infections. PASC were reported in 67.8% of cases, consisted predominantly in fatigue, dyspnea and concentration deficit, persisted in 60% over the follow-up period of on average eight months and their resolution was unaffected by post-infection vaccination. PASC was not associated with post-COVID-19 autoantibodies, but with elevated levels of IL-1ß, IL-6 and TNF-α. Blood profiling and single-cell data from validation cohorts with early infection suggested the induction of these cytokines in COVID-19 lung pro-inflammatory macrophages creating a self-sustaining feedback loop. Our data indicate a long-lasting cytokine triad -potentially underlying PASC symptoms - to be driven by macrophage primed during infection. We demonstrate how the combination of digital epidemiology with selective biobanking can rapidly generate hints towards disease mechanisms.

Persistent serum protein signatures define an inflammatory subset of long COVID

“…Lastly, the broader diversity of disease severity in the INCOV cohort compared to our mild to moderate cohort, allowed us to make an association between the clinical measure of acute disease severity (WHO ordinal scale score) and proteomic inflammatory signatures. Interestingly, INCOV patients from cluster E predominantly exhibited an acute WHO ordinal score of ≥3 reflecting the association between more severe acute disease and persistent inflammation 15 These findings substantially extend previous observations that have variably reported increased expression of IFN-γ, IFN-β, IFN-λ1/2/3, TNF, IL-6, IL-1β, and PTX3 in plasma from PASC patients using targeted cytokine panels [16][17][18] . While previous studies grouped all PASC participants, we provide the first evidence that more than half of all PASC have an inflammatory protein signature while others do not have this signature.…”

Tissue injury and leukocyte changes in post-acute sequelae of SARS-CoV-2: review of 2833 post-acute patient outcomes per immune dysregulation and microbial translocation in long COVID

“…It was reported that cytokine levels (i.e., IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17) remained elevated in persons at 2 weeks after recovery from acute COVID-19 symptoms (n=33) when compared with healthy donors (n=28) (64). A summary of data supporting high cytokine levels (especially IL-1β, IL-6 and TNF) (127) in PASC is shown in Table 1. Several reports have documented dysregulated cytokine levels.…”

Exercise is the Most Important Medicine for COVID-19

“…Initial inflammation during COVID-19 infection causes the release of pro-inflammatory cytokines (IL-6, TNF-a) (2,51) and recruitment of peripheral immune cells. This induces more tissue injury and in severe cases, leads to cytokine storm that consequently kills T cells and delayed/or suppressed B cell-mediated humoral response (2).…”