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The host gene classifier built on such a signature exhibited potential for diagnosing COVID-19 (AUC of 0.75-0.89) and indicating disease severity. Conclusions Compared to those with non-COVID-19 pneumonias, COVID-19 patients appeared to have a more disrupted airway microbiome with frequent potential concurrent infections, and a special trigger host immune response in certain pathways such as interferon gamma signaling. The immune-associated host transcriptional signatures of COVID-19 hold promise as a tool for improving COVID-19 diagnosis