Decreased serum levels of inflammaging marker miR-146a are associated with clinical response to tocilizumab in COVID-19 patients

Abstract

Background. Current COVID-19 pandemic poses an unprecedented threat to global health and healthcare systems. At least in western countries, the most amount of the death toll is accounted by old people affected by age-related diseases. In this regard, we proposed that COVID-19 severity may be tightly related to inflammaging, i.e. the age-related onset of inflammation, which is responsible for age-related diseases. It has been reported that systemic hyper-inflammation may turn to be detrimental in COVID-19 patients. Objective. Here, we exploited a recently closed clinical trial (NCT04315480) on the anti-IL-6 drug tocilizumab to assess whether microRNAs regulating inflammaging can be assessed as biomarkers of drug response and outcome. Methods. Serum levels of miR-146a-5p, -21-5p, and -126-3p were quantified by RT-PCR and Droplet Digital PCR by two independent laboratories on 30 patients with virologically confirmed COVID-19, characterized by multifocal interstitial pneumonia confirmed by CT-scan and requiring oxygen therapy, and 29 age- and gender-matched healthy control subjects. COVID-19 patients were treated with a single-dose intravenous infusion of 8 mg/kg tocilizumab and categorized into responders and non-responders. Results. We showed that COVID-19 patients who did not respond to tocilizumab have lower serum levels of miR-146a-5p after the treatment (p=0.007). Moreover, among non-responders, those with the lowest serum levels of miR-146a-5p experienced the most adverse outcome (p=0.008). Conclusion. Our data show that blood-based biomarkers, such as miR-146a-5p, can provide a molecular link between inflammaging and COVID-19 clinical course, thus allowing to enlarge the drug armory against this worldwide health threat.

MicroRNAs as biomarkers of coronavirus disease 2019 (COVID-19): a scoping review

“…In addition, no relevant studies were identi ed by searching the reference lists of the selected studies. After careful full-text reading, only seven studies [22][23][24][25][26][27][28] met the inclusion criteria and thus were included in the review. A owchart of the literature search is shown in Figure 1.…”

“…The characteristics of the seven studies included in this scoping review are summarized in Table 1. All seven studies were published in English, reported between October 2020 and January 2021, and published as research articles [22][23][24][25][26][27][28]. Four of them were conducted in China [23][24][25][26].…”

“…Four of them were conducted in China [23][24][25][26]. Six studies were conducted in humans [23][24][25][26][27][28] and one in an animal model [22]. Of the six human studies, ve compared patients with COVID-19 with healthy volunteers [23][24][25]27,28].…”

“…Six studies were conducted in humans [23][24][25][26][27][28] and one in an animal model [22]. Of the six human studies, ve compared patients with COVID-19 with healthy volunteers [23][24][25]27,28]. Three studies strati ed the group of patients with COVID-19 into severity subgroups [24][25][26]; while one included only patients with mild/moderate disease [23], the other two included only severe/critically ill patients [27,28].…”

Systematic Review of microRNAs in the SARS-CoV-2 Infection: Are microRNAs Potential Therapy for COVID-19?

“…MiRNAs have been revealed to play crucial roles in a complex network of interaction that don't respond to the tocilizumab treatment, the levels of miR-146a-5p were decreased in their serum. MiRNAs in the blood, such as miR-146a-5p, -21-5p, and -126-3p can be potential biomarkers to provide a molecular link between inflammation and the COVID-19 [20]. In an experimental study on rat and human derived cardiomyocytes, it has been shown that both ACE2 mRNA and protein levels are inhibited by miR-200c, which can also be the potential target of the miRNA therapeutics in cardiomyocyte-affected infections [21].…”