Recent studies have indicated that SARS-CoV-2 infection of human macrophages derived from induced pluripotent stem cells can reinforce ISG15 secretion via the deISGylating activity of the viral papain-like protease, which in turn contributes to aberrant macrophage activation and excessive production of proinflammatory cytokines; therefore, extracellular non-conjugated ISG15 can act as a cytokine to exacerbate inflammation in severe COVID-19 (15, 16, 62). This evidence concerns the gene ISG15 and COVID-19.