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Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is required for understanding skewed immune responses and finding outcome predictors. Here, we performed a longitudinal multi-omics study using a two-centre cohort of 14 patients. We analysed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of IFN-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signalling. Megakaryocyte- and erythroid cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond classical immune cells and may serve as an entry point to develop biomarkers and targeted treatments of patients with COVID-19.