{"doi":"10.1172/jci.insight.147610","title":"Cell-free DNA maps COVID-19 tissue injury and risk of death and can cause tissue injury","abstract":"INTRODUCTIONThe clinical course of coronavirus 2019 (COVID-19) is heterogeneous, ranging from mild to severe multiorgan failure and death. In this study, we analyzed cell-free DNA (cfDNA) as a biomarker of injury to define the sources of tissue injury that contribute to such different trajectories.METHODSWe conducted a multicenter prospective cohort study to enroll patients with COVID-19 and collect plasma samples. Plasma cfDNA was subject to bisulfite sequencing. A library of tissue-specific DNA methylation signatures was used to analyze sequence reads to quantitate cfDNA from different tissue types. We then determined the correlation of tissue-specific cfDNA measures to COVID-19 outcomes. Similar analyses were performed for healthy controls and a comparator group of patients with respiratory syncytial virus and influenza.RESULTSWe found markedly elevated levels and divergent tissue sources of cfDNA in COVID-19 patients compared with patients who had influenza and/or respiratory syncytial virus and with healthy controls. The major sources of cfDNA in COVID-19 were hematopoietic cells, vascular endothelium, hepatocytes, adipocytes, kidney, heart, and lung. cfDNA levels positively correlated with COVID-19 disease severity, C-reactive protein, and D-dimer. cfDNA profile at admission identified patients who subsequently required intensive care or died during hospitalization. Furthermore, the increased cfDNA in COVID-19 patients generated excessive mitochondrial ROS (mtROS) in renal tubular cells in a concentration-dependent manner. This mtROS production was inhibited by a TLR9-specific antagonist.CONCLUSIONcfDNA maps tissue injury that predicts COVID-19 outcomes and may mechanistically propagate COVID-19-induced tissue injury.FUNDINGIntramural Targeted Anti-COVID-19 grant, NIH.","journal":"JCI Insight","year":2021,"id":147572,"datarank":0.7555428903620446,"base_score":5.0369526024136295,"endowment":5.0369526024136295,"self_citation_contribution":0.7555428903620446,"citation_network_contribution":0.0,"self_endowment_contribution":0.7555428903620446,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":153,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8731,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":627890,"name":"Takayuki Tsuji","orcid":"0000-0003-3120-5562","position":1,"is_corresponding":false},{"id":268695,"name":"Fayaz Seifuddin","orcid":"0000-0003-3357-7888","position":2,"is_corresponding":false},{"id":246494,"name":"Moon Kyoo Jang","orcid":"0000-0002-1657-2877","position":3,"is_corresponding":false},{"id":289010,"name":"Peter S.T. Yuen","orcid":"0000-0001-9557-3909","position":4,"is_corresponding":false},{"id":627891,"name":"Hyesik Kong","orcid":"0000-0001-7540-2045","position":5,"is_corresponding":false},{"id":421967,"name":"Ilker Tunc","orcid":"0000-0001-5699-7549","position":6,"is_corresponding":false},{"id":268700,"name":"Komudi Singh","orcid":"0000-0002-6413-541X","position":7,"is_corresponding":false},{"id":627892,"name":"Ananth Charya","orcid":"0000-0002-9366-1515","position":8,"is_corresponding":false},{"id":391138,"name":"Kenneth J. Wilkins","orcid":"0000-0003-0531-7165","position":9,"is_corresponding":false},{"id":552234,"name":"Steven D. Nathan","orcid":"0000-0002-6270-1617","position":10,"is_corresponding":false},{"id":355240,"name":"Andrea L. Cox","orcid":"0000-0002-9331-2462","position":11,"is_corresponding":false},{"id":268694,"name":"Mehdi Pirooznia","orcid":"0000-0002-4210-6458","position":12,"is_corresponding":false},{"id":461361,"name":"Robert A. Star","orcid":"0000-0003-0940-3079","position":13,"is_corresponding":false},{"id":246493,"name":"Sean Agbor-Enoh","orcid":"0000-0002-9380-9161","position":14,"is_corresponding":false},{"id":627889,"name":"T. Andargie","orcid":"0000-0003-2888-1316","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:42:35.448762Z","pmid":"33651717","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}