Abstract Identifying additional risk factors for COVID-19 severity in numerous previously healthy patients without canonical clinical risk factors remains challenging. In this study, we investigate whether clonal hematopoiesis of indeterminate potential (CHIP), a common aging-related process that predisposes various inflammatory responses, may exert COVID-19 severity. We examine the clinical impact of CHIP in 143 laboratory-confirmed COVID-19 patients. Both stratified analyses and logistic regression including the interaction between canonical risk factors and CHIP show that CHIP is an independent risk factor for severe COVID-19, especially in previously healthy patients. Analyses of 60,310 single-cell immune transcriptome profiles identify distinct immunological signatures for CHIP (+) severe COVID-19 patients, particularly in classical monocytes, with a marked increase in pro-inflammatory cytokine responses and potent IFN-γ mediated hyperinflammation signature. We further demonstrate that the enhanced expression of CHIP (+) specific IFN-γ response genes is attributed to the CHIP mutation-dependent epigenetic reprogramming of poised or bivalent cis -regulatory elements. Our results highlight a unique immunopathogenic mechanism of CHIP in the progression of severe COVID-19, which could be extended to elucidate how CHIP contributes to a variety of human infectious diseases.

Clinical and immunological signatures of severe COVID-19 in previously healthy patients with clonal hematopoiesis