{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:29:53Z","timestamp":1793316593647,"version":"4.5.0"},"reference-count":102,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>A cytokine storm is a hyperinflammatory state secondary to the excessive production of cytokines by a deregulated immune system. It manifests clinically as an influenza-like syndrome, which can be complicated by multi-organ failure and coagulopathy, leading, in the most severe cases, even to death. The term cytokine storm was first used in 1993 to describe the graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. It was then reused to define the adverse syndromes secondary to the administration of immunostimulating agents, such as anti-CD28 antibodies or bioengineered immune cells, i.e., CAR T-cell therapy. Currently, the concept of cytokine storm has been better elucidated and extended to the pathogenesis of many other conditions, such as sepsis, autoinflammatory disease, primary and secondary hemophagocytic lymphohistiocytosis, and multicentric Castleman disease. Moreover, cytokine storm has recently emerged as a key aspect in the novel Coronavirus disease 2019, as affected patients show high levels of several key pro-inflammatory cytokines, such as IL-1, IL-2, IL-6, TNF-\u03b1, IFN-\u03b3, IP-10, GM-CSF, MCP-1, and IL-10, some of which also correlate with disease severity. Therefore, since the onset of the pandemic, numerous agents have been tested in the effort to mitigate the cytokine storm in COVID-19 patients, some of which are effective in reducing mortality, especially in critically ill patients, and are now becoming standards of care, such as glucocorticoids or some cytokine inhibitors. However, the challenge is still far from being met, and other therapeutic strategies are being tested in the hope that we can eventually overcome the disease.<\/jats:p>","DOI":"10.3390\/medicina58020144","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T22:46:32Z","timestamp":1642545992000},"page":"144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":319,"title":["Cytokine Storm in COVID-19: Immunopathogenesis and Therapy"],"prefix":"10.3390","volume":"58","author":[{"given":"Christian","family":"Zanza","sequence":"first","affiliation":[{"name":"Foundation \u201cOspedale Alba-Bra Onlus\u201d, 12060 Verduno, Italy"},{"name":"Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy"},{"name":"Department of Emergency Medicine, Policlinico Gemelli\/IRCCS University of Catholic of Sacred Heart, 00168 Rome, Italy"},{"name":"Research Training Innovation Infrastructure, Research and Innovation Department, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsiana","family":"Romenskaya","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio and Cesare Arrigo Hospital, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-028X","authenticated-orcid":false,"given":"Alice","family":"Manetti","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, and Molecular Pathology and Critical Care Medicine, Institute of Legal Medicine, University of Pisa, via Roma 55, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Franceschi","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Policlinico Gemelli\/IRCCS University of Catholic of Sacred Heart, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3433-7122","authenticated-orcid":false,"given":"Raffaele","family":"La Russa","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8179-1072","authenticated-orcid":false,"given":"Giuseppe","family":"Bertozzi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniello","family":"Maiese","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, and Molecular Pathology and Critical Care Medicine, Institute of Legal Medicine, University of Pisa, via Roma 55, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8679-5435","authenticated-orcid":false,"given":"Gabriele","family":"Savioli","sequence":"additional","affiliation":[{"name":"Emergency Medicine and Surgery, IRCCS Fondazione Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3178-0797","authenticated-orcid":false,"given":"Gianpietro","family":"Volonnino","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8831-1361","authenticated-orcid":false,"given":"Yaroslava","family":"Longhitano","sequence":"additional","affiliation":[{"name":"Foundation \u201cOspedale Alba-Bra Onlus\u201d, 12060 Verduno, Italy"},{"name":"Department of Emergency Medicine, Anesthesia and Critical Care Medicine, Michele and Pietro Ferrero Hospital, 12060 Verduno, Italy"},{"name":"Research Training Innovation Infrastructure, Research and Innovation Department, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy"},{"name":"Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio and Cesare Arrigo Hospital, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1146\/annurev-immunol-032414-112227","article-title":"Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling","volume":"33","author":"Canna","year":"2015","journal-title":"Annu. 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