Elevated levels of Activin A and FLRG link to the worst results in hard COVID-19

Infectious disease of coronavirus respiratory syndrome 2 (SARS-CoV-2) causes “cytokine storm” in hospitalized patients and ICU. Studies have shown that inhibition of cytokine signaling and steroid treatment helps to achieve positive outcomes in patients. However, a better understanding of the downstream signaling pathways that contribute to the large immune response is critical for the treatment of patients suffering from severe COVID-19 symptoms.

Analyzing the response of COVID-19 relevant cell types to inflammatory cytokines released during the cytokine storm

Researchers from the US recently tested serum from COVID-19 patients to see if they had elevated Activin A levels. They also evaluated PAI-1, another signal found to be associated with ARDS, and one of the parameters reported to be associated with ARDS-related mortality. They further determined whether the levels of Activin A, a follistatin-associated gene (FLRG) and PAI were linked to key COVID-19 disease markers such as supplemental oxygen requirement, ARDS symptoms, and mortality. The review is published on the preprint server bioRxiv*.

The researchers had previously studied IL-1 and TNFα in skeletal muscle cachexia, where the cytokines induce skeletal muscle atrophy. They learned from their previous studies that IL-1 and TNFα could induce Activin A production in skeletal muscle, which causes skeletal muscle atrophy. They felt this was relevant in the context of COVID-19, and it was previously reported. Earlier, high levels of Activin A were reported to be detected in bronchial alveolar lava fluid in patients with severe respiratory tract syndrome (ARDS).

“The view, therefore, is that these adversely affected patients do not suffer directly from the viral load, but instead from excessive reactivation of the immune system – the cytokine response that occurs later, which in some patients overdoses on Activin A. “

High levels of Activin A and FLRG were baseline predictors of severe COVID-19 side effects

In the present study, the researchers wanted to see if other relevant COVID-19 cell types such as bronchial and pulmonary smooth muscle responded in a similar way to inflammatory cytokines released during Cytokine storm to produce Activin A.. They had been tested with COVID -19 patients using Regeneron antibody anti-IL-6R in which they evaluated the serum of these patients after randomization and before treatment to determine baseline levels of Activin A, PAI-1, and measuring FLRG. They then linked these values ​​to underlying clinical and laboratory variables and key disease outcomes.

The results of the study showed that cytokines responsible for activating the NF-kappaβ pathway may also activate Activin A and the downstream signal, FLRG. In hospitalized COVID-19 patients, high levels of Activin A / FLRG were at the baseline predictors of COVID-19 side effects, such as the need for ventilation and overall mortality. Patients with above-average levels of Activin A / FLRG were nearly three times more likely to die compared to patients whose Activin A / FLRG levels were below the sample average.

Inhibition of Activin A may be beneficial in the treatment of COVID-19 patients with ARDS

The results show that both Activin A and FLRG were significantly upregulated in COVID-19 patients in the ICU. Some patients experienced a more than double increase in Activin A. Interestingly, Activin A levels were not significantly increased in severe COVID-19 patients who did not require aggressive mechanical ventilation indicating that the signal between -strict clearing of patient numbers.

While FLRG levels increased in patients with severe non-ICU disease, it was even higher in ICU patients, especially those with ARDS and requiring aggressive mechanical ventilation. In addition, subjects with very high elevations of FLRG were also found to be more likely to require aggressive ventilation. Thus, high levels of Activin A and FLRG increase the risk of ARDS in COVID-19 patients, and inhibition of Activin A may be beneficial in the treatment of COVID-19 patients with ARDS.

“We, therefore, recommend that it is reasonable to try to block Activin A or its stimulant pathway to treat COVID-19 patients with ARDS.”

* Important message

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be seen as final, guiding health-related clinical / behavioral practice, or treated as fixed information.