Therefore, the aims of the present study were (i) identification of host signatures on the transcriptomic level for risk assessment and prognostic potential in COVID-19 patients using comprehensive NGS-based RNA-Seq analyses of survivors and non-survivors at the ICU, (ii) to compare RNA-signatures with standard of care diagnostics including C-reactive protein (CRP), procalcitonin (PCT), and sequential organ failure assessment (SOFA) score as well as to (iii) establish an easy to implement RT-qPCR approach for identified prognostic transcripts. This evidence concerns the gene CRP and COVID-19.