The IL-1ß, IL-6 and TNF-α Cytokine Triad Is Associated With Post-Acute Sequelae of COVID-19


new study by researchers from Martin Luther University Halle-Wittenberg-Germany has found that the IL-1ß, IL-6 and TNF-α cytokine triad is associated with post-acute sequelae of COVID-19 (PASC) or Long COVID.

The study findings were published on a preprint server of the Lancet and are currently being peer reviewed.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new virus causing coronavirus disease 2019 (COVID-19) which has led to a health crisis of global scale. COVID-19 is now recognized as a multi-organ disease with considerable mortality in risk groups1-3.

With a growing population of recovering patients, it became clear that in 32-87% of patients (including those with mild acute disease) health impairments persist beyond the acute phase of infection 4-7.

The most common definition of such post-acute sequelae of COVID-19 (PASC) is persistence of symptoms beyond four weeks 4,5.

The clinical spectrum of PASC includes fatigue and exercise intolerance, brain fog, shortness of breath, joint pain, fever, sleep and anxiety disorders as well as gastrointestinal symptoms and palpitations 4-6. Symptoms may persist for months and their severity can range from mild to debilitating.

The immense numbers of COVID-19 survivors with post-infection disability that prevent these individuals to return to normal active life added another layer in this health crisis beyond the threat of exhausting intensive care unit capacities. Given 250 million SARS-CoV-2 infections counted globally until November 2021 by the WHO, the impact of PASC will likely be profound.

This hypothesis has been fueled by the observation that some infected patients do not rapidly clear the virus 9,10, which is in line with the observation that post-acute viral persistance is a relatively common feature of RNA viruses (e.g. Ebola and HCV) and has also been discussed in the context of chronic symptoms or reactivated disease 11.

Yet, direct evidence pointing to a role of such potential reservoirs in PASC as well as on the effects of their eradication e.g. via post-infection vaccination is currently lacking.

Another potential biological correlate of PASC may be autoimmune tissue damage. Already in the early phases of the pandemic, it became obvious that the SARS-CoV-2 virus shifts adaptive immunity towards autoreactivity 12,13.

There is now a large body of evidence that diverse autoantibody classes are produced in acute COVID-19 as well as post-COVID-19 multisystem inflammatory syndrome in children 13-17. Moreover, many reports suggest that patients may experience de novo or worsening of preexisting autoimmune conditions such as autoimmune cytopenias, Guillain-Barré syndrome or systemic lupus erythematodes 18.

It remains elusive, however, if autoantibodies represent an inflammatory epiphenomenon or pathophysiologically contribute to PASC 19.

Quickly closing the knowledge gap on PASC pathophysiology is one of the current global priorities. Here, we show how

the combination of digital epidemiology with selective biobanking can rapidly generate hints towards disease mechanisms. Using this approach, we rapidly identified and recruited a large cohort allowing dedicated analyses of biomaterial in a subsample of previously infected participants with or without PASC.

Our analyzes provide evidence for a long-lasting cytokine signature consisting of elevated levels of IL-1ß, IL-6 and TNF-α that potentially underlie many of the clinical symptoms of PASC and that may derive from the macrophage compartment.


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