Abstract
Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.
【초록키워드】 SARS-CoV-2, Efficacy, platelet activation, Baricitinib, Cytokine storm, Randomized controlled trials, Mortality, Antiviral, Pneumonia, antivirals, interferon, cytokine, outcome, elderly patients, viral entry, Replication, adverse events, Cohort, RNA-Seq, Viral, Culture, cells, controlled trials, Microscopy, Patient, SARS-CoV-2 pneumonia, inhibitor, ACE2 expression, host proteins, Janus kinase, kinases, liver cells, parenchymal cells, 95% CI, janus, median age, host protein, human liver, viral load quantification, benefit, Cell, greater, inhibited, increase, reveal, moderate-severe, parenchymal, the cytokine storm, 【제목키워드】 SARS-CoV-2, morbidity and mortality, Jak, liver, Inflammatory response, modulate, reduce,