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We identified molecular changes in the sera of COVID-19 patients compared to other groups implicating dysregulation of macrophage, platelet degranulation, complement system pathways, and massive metabolic suppression. Targeted proteomics and metabolomics assays were employed to further validate this molecular classifier in a second test cohort of 19 COVID-19 patients, leading to 16 correct assignments. The model was validated using 10 independent patients, 7 of which were correctly classified. We then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients. Here, we performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control individuals. Electronic address: detection and effective treatment of severe COVID-19 patients remain major challenges. Electronic address: 7 Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China. Electronic address: 6 Taizhou Hospital, Wenzhou Medical University, 150 Ximen Street, Linhai 317000, Zhejiang Province, China. Electronic address: 5 Calibra Lab at DIAN Diagnostics, 329 Jinpeng Street, Hangzhou 310030, Zhejiang Province, China. 4 Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.

3 Calibra Lab at DIAN Diagnostics, 329 Jinpeng Street, Hangzhou 310030, Zhejiang Province, China.2 Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.1 Taizhou Hospital, Wenzhou Medical University, 150 Ximen Street, Linhai 317000, Zhejiang Province, China.