Early administration of tofacitinib in COVID-19 pneumonitis: An open randomised controlled trial.

BACKGROUND: Controversies on sub-populations most sensitive to therapy and the best timing of starting the treatment still surround the use of immunomodulatory drugs in COVID-19. OBJECTIVES: We designed a multicentre open-label randomised controlled trial to test the effect of prompt adding of tofacitinib to standard therapy for hospitalised patients affected by mild/moderate COVID-19 pneumonitis. METHODS: Patients admitted to three Italian hospitals affected by COVID-19 pneumonitis not requiring mechanical ventilation were randomised to receive standard treatment alone or tofacitinib (10 mg/bid) for 2 weeks, starting within the first 24 h from admission. RESULTS: A total of 116 patients were randomised; 49 in the experimental arm completed the 14-day treatment period, 9 discontinued tofacitinib as the disease worsened and were included in the analysis, and 1 died of respiratory failure. All 58 control patients completed the study. Clinical and demographic characteristics were similar between the study groups. In the tofacitinib group, 9/58 (15.5%) patients progressed to noninvasive ventilation (CPAP) to maintain SO2 > 93%, invasive mechanical ventilation or death by day 14 was 15.5%, significantly less than in the control group (20/58, 34.4%, RR 0,45, RRR -55%, NNT 5; p = .018). No differences in severe adverse effect incidence had been observed across the groups. CONCLUSION: High-dose tofacitinib therapy in patients with COVID pneumonitis is safe and may prevent deterioration to respiratory failure.

Circulating miR-320b and miR-483-5p levels are associated with COVID-19 in-hospital mortality.

The stratification of mortality risk in COVID-19 patients remains extremely challenging for physicians, especially in older patients. Innovative minimally invasive molecular biomarkers are needed to improve the prediction of mortality risk and better customize patient management. In this study, aimed at identifying circulating miRNAs associated with the risk of COVID-19 in-hospital mortality, we analyzed serum samples of 12 COVID-19 patients by small RNA-seq and validated the findings in an independent cohort of 116 COVID-19 patients by qRT-PCR. Thirty-four significantly deregulated miRNAs, 25 downregulated and 9 upregulated in deceased COVID-19 patients compared to survivors, were identified in the discovery cohort. Based on the highest fold-changes and on the highest expression levels, 5 of these 34 miRNAs were selected for the analysis in the validation cohort. MiR-320b and miR-483-5p were confirmed to be significantly hyper-expressed in deceased patients compared to survived ones. Kaplan-Meier and Cox regression models, adjusted for relevant confounders, confirmed that patients with the 20% highest miR-320b and miR-483-5p serum levels had three-fold increased risk to die during in-hospital stay for COVID-19. In conclusion, high levels of circulating miR-320b and miR-483-5p can be useful as minimally invasive biomarkers to stratify older COVID-19 patients with an increased risk of in-hospital mortality.

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

Current COVID-19 pandemic poses an unprecedented threat to global health and healthcare systems. The most amount of the death toll is accounted by old people affected by age-related diseases that develop a hyper-inflammatory syndrome. In this regard, we hypothesized that COVID-19 severity may be linked to inflammaging. Here, we examined 30 serum samples from patients enrolled in the clinical trial NCT04315480 assessing the clinical response to a single-dose intravenous infusion of the anti-IL-6 receptor drug Tocilizumab (TCZ) in COVID-19 patients with multifocal interstitial pneumonia. In these serum samples, as well as in 29 age- and gender-matched healthy control subjects, we assessed a set of microRNAs that regulate inflammaging, i.e. miR-146a-5p, miR-21-5p, and miR-126-3p, which were quantified by RT-PCR and Droplet Digital PCR. We showed that COVID-19 patients who did not respond to TCZ have lower serum levels of miR-146a-5p after the treatment (p = 0.007). Among non-responders, those with the lowest serum levels of miR-146a-5p experienced the most adverse outcome (p = 0.008). Our data show that a blood-based biomarker, such as miR-146a-5p, can provide clues about the molecular link between inflammaging and COVID-19 clinical course, thus allowing to better understand the use of biologic drug armory against this worldwide health threat.