Comprehensive and unbiased re-analysis of published blood transcriptome data from patients of COVID-19 reveals significant up-regulation of the gene set functional in NETosis, but no evidence of general "cytokine storm". In severe COVID-19 illness, there is significant up-regulation of complement and coagulation pathway, and negative correlation between NETosis and respiratory function (oxygen saturation). Interestingly, there is an early spike in the level of IL-6 gene expression in severe illness compared to moderate illness. With passing days post-onset, the level of IL-6 expression in severe illness approaches that in moderate illness. The data are consistent with IL-6 acting as a driver of NETosis in the early phase of severe COVID-19 illness, that results in a vicious cycle of NETosis-complement/coagulation-respiratory dysfunction. This has important consequence for timing of rational therapy with anti-IL-6 and NETosis inhibitors in severe COVID-19 illness.
