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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,12,3]]},"abstract":"<jats:p>Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying of SARS-CoV-2. Subsets of the 100 top-upregulated genes in nasal swabs are upregulated in the heart, lung, kidney, and liver, but not mediastinal lymph nodes. Twenty-two of these are \u201cnoncanonical\u201d immune genes, which we link to components of the renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, and mitochondrial dysfunction. Immunohistochemistry of mediastinal lymph nodes reveals altered architecture, excess collagen deposition, and pathogenic fibroblast infiltration. Many of the above findings are paralleled in animal models of SARS-CoV-2 infection and human peripheral blood mononuclear and whole blood samples from individuals with early and later SARS-CoV-2 variants. We then redefine cytokine storm in lethal COVID-19 as driven by upstream immune gene and mitochondrial signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation and organ damage, including compromised mediastinal lymph node function.<\/jats:p>","DOI":"10.1073\/pnas.2401968121","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:13:52Z","timestamp":1732709632000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":24,"title":["Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes"],"prefix":"10.1073","volume":"121","author":[{"given":"Michael J.","family":"Topper","sequence":"first","affiliation":[{"name":"COVID-19 International Research Team, Medford, MA 02155"},{"name":"Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph W.","family":"Guarnieri","sequence":"additional","affiliation":[{"name":"COVID-19 International Research Team, Medford, MA 02155"},{"name":"The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104"},{"name":"Center for Mitochondrial and Epigenomic Medicine, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Haltom","sequence":"additional","affiliation":[{"name":"COVID-19 International Research Team, Medford, MA 02155"},{"name":"The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104"},{"name":"Center for Mitochondrial and Epigenomic Medicine, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9499-8638","authenticated-orcid":false,"given":"Amy","family":"Chadburn","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Cope","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Nottingham, Derby DE22 3DT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Frere","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine, Mount Sinai, New York, NY 10023"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"An","sequence":"additional","affiliation":[{"name":"COVID-19 International Research Team, Medford, MA 02155"},{"name":"Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Borczuk","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saloni","family":"Sinha","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JangKeun","family":"Kim","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwoon","family":"Park","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Butler","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cem","family":"Meydan","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Foox","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaron","family":"Bram","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A.","family":"Richard","sequence":"additional","affiliation":[{"name":"Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University, Bethesda, MD 20814"},{"name":"Henry M. 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