{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T23:04:24Z","timestamp":1787871864121,"version":"build-2784847793"},"reference-count":158,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T00:00:00Z","timestamp":1617840000000},"content-version":"unspecified","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,3,23]]},"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:p>The ongoing pandemic caused by the novel coronavirus SARS-CoV-2 has disrupted the global economy and strained healthcare systems to their limits. After the virus first emerged in late 2019, the first intervention that demonstrated significant reductions in mortality for severe COVID-19 in large-scale trials was corticosteroids. Additional options that may reduce the burden on the healthcare system by reducing the number of patients requiring intensive care unit support are desperately needed, yet no therapy has conclusively established benefit in randomized studies for the management of moderate or mild cases of disease. Severe COVID-19 disease is characterized by a respiratory distress syndrome accompanied by elevated levels of several systemic cytokines, in a profile that shares several features with known inflammatory pathologies such as hemophagocytic lymphohistiocytosis and cytokine release syndrome secondary to chimeric antigen receptor (CAR) T cell therapy. Based on these observations, modulation of inflammatory cytokines, particularly interleukin (IL)-6, was proposed as a strategy to mitigate severe disease. Despite encouraging recoveries with anti-IL-6 agents, especially tocilizumab from single-arm studies, early randomized trials returned mixed results in terms of clinical benefit with these interventions. Later, larger trials such as RECOVERY and REMAP-CAP, however, are establishing anti-IL-6 in combination with steroids as a potential option for hypoxic patients with evidence of hyperinflammation. We propose that a positive feedback loop primarily mediated by macrophages and monocytes initiates the inflammatory cascade in severe COVID-19, and thus optimal benefit with anti-IL-6 therapies may require intervention during a finite window of opportunity at the outset of hyperinflammation but before fulminant disease causes irreversible tissue damage\u2014as defined clinically by C reactive protein levels higher than 75\u2009mg\/L.<\/jats:p>","DOI":"10.1136\/jitc-2020-002285","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T12:42:29Z","timestamp":1617972149000},"page":"e002285","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["IL-6 modulation for COVID-19: the right patients at the right time?"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct04409262","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04401579","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04443881","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04362111","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04643678","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04421027","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04373044","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04321993","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04640168","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8322-475X","authenticated-orcid":false,"given":"Paolo Antonio","family":"Ascierto","sequence":"first","affiliation":[{"name":"Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binqing","family":"Fu","sequence":"additional","affiliation":[{"name":"Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center; Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center; Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"2025100314442381000_9.4.e002285.1","unstructured":"JohnsHopkins . Mortality analyses - Johns Hopkins Coronavirus resource center: JohnsHopkins, 2020. Available: https:\/\/coronavirus.jhu.edu\/data\/mortality"},{"key":"2025100314442381000_9.4.e002285.2","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1016\/S1473-3099(20)30484-9","article-title":"Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics","volume":"20","author":"Petersen","year":"2020","journal-title":"Lancet Infect Dis"},{"key":"2025100314442381000_9.4.e002285.3","doi-asserted-by":"crossref","unstructured":"Rossen LM BA , Ahmad FB , Sutton P , et al . Excess deaths associated with COVID-19, by age and race and ethnicity \u2014 United States, January 26\u2013October 3, 2020 | MMWR. Morb Mortal Wkly Rep;2020:1522\u20137.","DOI":"10.15585\/mmwr.mm6942e2"},{"key":"2025100314442381000_9.4.e002285.4","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s43018-020-0074-y","article-title":"The impact of the COVID-19 pandemic on cancer care","volume":"1","author":"Richards","year":"2020","journal-title":"Nature Cancer"},{"key":"2025100314442381000_9.4.e002285.5","doi-asserted-by":"crossref","first-page":"3914","DOI":"10.1200\/JCO.20.01580","article-title":"COVID-19 severity and outcomes in patients with cancer: a matched cohort study","volume":"38","author":"Brar","year":"2020","journal-title":"J Clin Oncol"},{"key":"2025100314442381000_9.4.e002285.6","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1200\/GO.20.00225","article-title":"Effect of cancer on clinical outcomes of patients with COVID-19: a meta-analysis of patient data","volume":"6","author":"Giannakoulis","year":"2020","journal-title":"JCO Glob Oncol"},{"key":"2025100314442381000_9.4.e002285.7","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/S1470-2045(20)30314-4","article-title":"COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study","volume":"21","author":"Garassino","year":"2020","journal-title":"Lancet Oncol"},{"key":"2025100314442381000_9.4.e002285.8","doi-asserted-by":"publisher","DOI":"10.1172\/jci137244"},{"key":"2025100314442381000_9.4.e002285.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0146736(20)30183-5"},{"key":"2025100314442381000_9.4.e002285.10","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1093\/cid\/ciaa272","article-title":"Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China","volume":"71","author":"Wang","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2025100314442381000_9.4.e002285.11","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1001\/jama.2020.5394","article-title":"Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy","volume":"323","author":"Grasselli","year":"2020","journal-title":"JAMA"},{"key":"2025100314442381000_9.4.e002285.12","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00547-2020"},{"key":"2025100314442381000_9.4.e002285.13","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1002\/oby.22859","article-title":"Association of obesity with disease severity among patients with coronavirus disease 2019","volume":"28","author":"Kalligeros","year":"2020","journal-title":"Obesity"},{"key":"2025100314442381000_9.4.e002285.14","doi-asserted-by":"crossref","unstructured":"Onder G , Rezza G , Brusaferro S . Case-Fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA 2020.doi:10.1001\/jama.2020.4683","DOI":"10.1001\/jama.2020.4683"},{"key":"2025100314442381000_9.4.e002285.15","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1002\/oby.22831","article-title":"High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation","volume":"28","author":"Simonnet","year":"2020","journal-title":"Obesity"},{"key":"2025100314442381000_9.4.e002285.16","doi-asserted-by":"publisher","DOI":"10.1016\/SO140-6736(20)30566-3"},{"key":"2025100314442381000_9.4.e002285.17","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd4585"},{"key":"2025100314442381000_9.4.e002285.18","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd4570"},{"key":"2025100314442381000_9.4.e002285.19","first-page":"e6","article-title":"Neutrophil-To-Lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19","volume":"81","author":"Liu","year":"2020","journal-title":"J Infect"},{"key":"2025100314442381000_9.4.e002285.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106504"},{"key":"2025100314442381000_9.4.e002285.21","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-016-0188-z"},{"key":"2025100314442381000_9.4.e002285.22","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jaci.2020.05.008","article-title":"Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19","volume":"146","author":"Herold","year":"2020","journal-title":"J Allergy and Immunol"},{"key":"2025100314442381000_9.4.e002285.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.07.009"},{"key":"2025100314442381000_9.4.e002285.24","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2026131"},{"key":"2025100314442381000_9.4.e002285.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102537"},{"key":"2025100314442381000_9.4.e002285.26","doi-asserted-by":"crossref","DOI":"10.1186\/s12916-020-01682-y","article-title":"Could hemophagocytic lymphohistiocytosis be the core issue of severe COVID-19 cases?","volume":"18","author":"Opoka-Winiarska","year":"2020","journal-title":"BMC Med"},{"key":"2025100314442381000_9.4.e002285.27","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1172\/JCI137647","article-title":"SARS-CoV-2: a storm is raging","volume":"130","author":"Pedersen","year":"2020","journal-title":"Journal of Clinical Investigation"},{"key":"2025100314442381000_9.4.e002285.28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2005615117"},{"key":"2025100314442381000_9.4.e002285.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2020.108393"},{"key":"2025100314442381000_9.4.e002285.30","unstructured":"Ascierto PA ea . SITC Statement on anti-IL-6\/IL-6R for COVID-19 - Society for Immunotherapy of Cancer (SITC), 2020. Available: https:\/\/www.sitcancer.org\/research\/covid-19-resources\/il-6-editorial"},{"key":"2025100314442381000_9.4.e002285.31","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.jmii.2020.02.012","article-title":"Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): facts and myths","volume":"53","author":"Lai","year":"2020","journal-title":"J Microbiol Immunol Infect"},{"key":"2025100314442381000_9.4.e002285.32","doi-asserted-by":"crossref","unstructured":"Mo P , Xing Y , Xiao Y , et al . Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin Infect Dis 2020.doi:10.1093\/cid\/ciaa270","DOI":"10.1093\/cid\/ciaa270"},{"key":"2025100314442381000_9.4.e002285.33","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.6775"},{"key":"2025100314442381000_9.4.e002285.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmaid.2020.101623"},{"key":"2025100314442381000_9.4.e002285.35","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1001\/jama.2020.19719","article-title":"Long-Term health consequences of COVID-19","volume":"324","author":"del Rio","year":"2020","journal-title":"JAMA"},{"key":"2025100314442381000_9.4.e002285.36","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1016\/j.jiph.2020.08.003","article-title":"Syndrome resembling Kawasaki disease in COVID-19 asymptomatic children","volume":"13","author":"Rehman","year":"2020","journal-title":"J Infect Public Health"},{"key":"2025100314442381000_9.4.e002285.37","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1016\/S0140-6736(20)31103-X","article-title":"An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study","volume":"395","author":"Verdoni","year":"2020","journal-title":"The Lancet"},{"key":"2025100314442381000_9.4.e002285.38","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202003-0543OC"},{"key":"2025100314442381000_9.4.e002285.39","unstructured":"Agarwal WKP . Chest imaging appearance of COVID-19 infection, 2020. Available: https:\/\/doiorg\/101148\/ryct2020200028"},{"key":"2025100314442381000_9.4.e002285.40","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1007\/s00134-020-06033-2","article-title":"COVID-19 pneumonia: different respiratory treatments for different phenotypes?","volume":"46","author":"Gattinoni","year":"2020","journal-title":"Intensive Care Med"},{"key":"2025100314442381000_9.4.e002285.41","doi-asserted-by":"crossref","first-page":"103455","DOI":"10.1016\/j.resp.2020.103455","article-title":"Distinct phenotypes require distinct respiratory management strategies in severe COVID-19","volume":"279","author":"Robba","year":"2020","journal-title":"Respir Physiol Neurobiol"},{"key":"2025100314442381000_9.4.e002285.42","doi-asserted-by":"crossref","first-page":"567672","DOI":"10.3389\/fpubh.2020.567672","article-title":"A pattern categorization of CT findings to predict outcome of COVID-19 pneumonia","volume":"8","author":"Jin","year":"2020","journal-title":"Frontiers in Public Health"},{"key":"2025100314442381000_9.4.e002285.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.02.01"},{"key":"2025100314442381000_9.4.e002285.44","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathological findings of COVID-19 associated with acute respiratory distress syndrome","volume":"8","author":"Xu","year":"2020","journal-title":"The Lancet Respiratory Medicine"},{"key":"2025100314442381000_9.4.e002285.45","doi-asserted-by":"crossref","first-page":"100434","DOI":"10.1016\/j.eclinm.2020.100434","article-title":"Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: a case series","volume":"24","author":"Rapkiewicz","year":"2020","journal-title":"EClinicalMedicine"},{"key":"2025100314442381000_9.4.e002285.46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2020.04.007","article-title":"Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases","volume":"220","author":"Magro","year":"2020","journal-title":"Translational Research"},{"key":"2025100314442381000_9.4.e002285.47","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1016\/S0140-6736(03)13413-7","article-title":"Lung pathology of fatal severe acute respiratory syndrome","volume":"361","author":"Nicholls","year":"2003","journal-title":"The Lancet"},{"key":"2025100314442381000_9.4.e002285.48","unstructured":"Bryce C , Grimes Z , Pujadas E . Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience. medRxiv 2020."},{"key":"2025100314442381000_9.4.e002285.49","doi-asserted-by":"crossref","unstructured":"Diao B , Wang C , Tan Y , et al . Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol 2020;11.doi:10.3389\/fimmu.2020.00827","DOI":"10.3389\/fimmu.2020.00827"},{"key":"2025100314442381000_9.4.e002285.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.052"},{"key":"2025100314442381000_9.4.e002285.51","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2003138117"},{"key":"2025100314442381000_9.4.e002285.52","doi-asserted-by":"crossref","unstructured":"Tang X , Yang M , Duan Z . Transferrin receptor is another receptor for SARS-CoV-2 entry. bioRxiv 2020.","DOI":"10.1101\/2020.10.23.350348"},{"key":"2025100314442381000_9.4.e002285.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13889-6"},{"key":"2025100314442381000_9.4.e002285.54","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)03640-2"},{"key":"2025100314442381000_9.4.e002285.55","doi-asserted-by":"publisher","DOI":"10.1002\/path.1570"},{"key":"2025100314442381000_9.4.e002285.56","doi-asserted-by":"crossref","first-page":"R45","DOI":"10.1530\/JOE-20-0260","article-title":"Endocrine aspects of ACE2 regulation: RaaS, steroid hormones and SARS-CoV-2","volume":"247","author":"Young","year":"2020","journal-title":"Journal of Endocrinology"},{"key":"2025100314442381000_9.4.e002285.57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/256294","article-title":"Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease","volume":"2012","author":"Tikellis","year":"2012","journal-title":"Int J Pept"},{"key":"2025100314442381000_9.4.e002285.58","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/S0140-6736(20)31305-2","article-title":"Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington state: a case series","volume":"396","author":"Bradley","year":"2020","journal-title":"The Lancet"},{"key":"2025100314442381000_9.4.e002285.59","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.cell.2020.05.042","article-title":"SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract","volume":"182","author":"Hou","year":"2020","journal-title":"Cell"},{"key":"2025100314442381000_9.4.e002285.60","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-0595-z"},{"key":"2025100314442381000_9.4.e002285.61","doi-asserted-by":"crossref","first-page":"103104","DOI":"10.1016\/j.ebiom.2020.103104","article-title":"Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology","volume":"61","author":"Bussani","year":"2020","journal-title":"EBioMedicine"},{"key":"2025100314442381000_9.4.e002285.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.04.021"},{"key":"2025100314442381000_9.4.e002285.63","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.2147\/IDR.S258639","article-title":"Role of Monocytes\/Macrophages in Covid-19 Pathogenesis: Implications for Therapy]]&gt","volume":"13","author":"G\u00f3mez-Rial","year":"2020","journal-title":"Infect Drug Resist"},{"key":"2025100314442381000_9.4.e002285.64","doi-asserted-by":"publisher","DOI":"10.7326\/M20-0533"},{"key":"2025100314442381000_9.4.e002285.65","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.12.758"},{"key":"2025100314442381000_9.4.e002285.66","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-04-703751"},{"key":"2025100314442381000_9.4.e002285.67","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.blre.2018.11.002","article-title":"Recent advances in car T-cell toxicity: mechanisms, manifestations and management","volume":"34","author":"Brudno","year":"2019","journal-title":"Blood Rev"},{"key":"2025100314442381000_9.4.e002285.68","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.12.756"},{"key":"2025100314442381000_9.4.e002285.69","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2595"},{"key":"2025100314442381000_9.4.e002285.70","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1111\/ped.13064","article-title":"Hemophagocytic lymphohistiocytosis: pathogenesis, diagnosis, and management","volume":"58","author":"Morimoto","year":"2016","journal-title":"Pediatrics International"},{"key":"2025100314442381000_9.4.e002285.71","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1097\/00043426-199302000-00012","article-title":"Hypercytokinemia in hemophagocytic syndrome","volume":"15","author":"Fujiwara","year":"1993","journal-title":"J Pediatr Hematol Oncol"},{"key":"2025100314442381000_9.4.e002285.72","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2015.1.190"},{"key":"2025100314442381000_9.4.e002285.73","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1002\/cncr.30084","article-title":"Malignancy-Associated hemophagocytic lymphohistiocytosis in adults: relation to hemophagocytosis, characteristics, and outcomes","volume":"122","author":"Tamamyan","year":"2016","journal-title":"Cancer"},{"key":"2025100314442381000_9.4.e002285.74","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12612"},{"key":"2025100314442381000_9.4.e002285.75","doi-asserted-by":"crossref","DOI":"10.1016\/j.cyto.2020.155365","article-title":"An inter-correlated cytokine network identified at the center of cytokine storm predicted COVID-19 prognosis","volume":"138","author":"Liu","year":"2021","journal-title":"Cytokine"},{"key":"2025100314442381000_9.4.e002285.76","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1002\/jmv.25948","article-title":"Elevated interleukin-6 and severe COVID-19: a meta-analysis","volume":"92","author":"Aziz","year":"2020","journal-title":"J Med Virol"},{"key":"2025100314442381000_9.4.e002285.77","doi-asserted-by":"crossref","first-page":"e594","DOI":"10.1016\/S2665-9913(20)30275-7","article-title":"COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study","volume":"2","author":"Manson","year":"2020","journal-title":"The Lancet Rheumatology"},{"key":"2025100314442381000_9.4.e002285.78","doi-asserted-by":"crossref","first-page":"e754","DOI":"10.1016\/S2665-9913(20)30343-X","article-title":"Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study","volume":"2","author":"Webb","year":"2020","journal-title":"The Lancet Rheumatology"},{"key":"2025100314442381000_9.4.e002285.79","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1002\/art.38690","article-title":"Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome","volume":"66","author":"Fardet","year":"2014","journal-title":"Arthritis & Rheumatology"},{"key":"2025100314442381000_9.4.e002285.80","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01792-08"},{"key":"2025100314442381000_9.4.e002285.81","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2007.02.007"},{"key":"2025100314442381000_9.4.e002285.82","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1093\/infdis\/jiaa724","article-title":"Monocyte CD169 expression as a biomarker in the early diagnosis of coronavirus disease 2019","volume":"223","author":"Bedin","year":"2021","journal-title":"J Infect Dis"},{"key":"2025100314442381000_9.4.e002285.83","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1093\/nsr\/nwaa041","article-title":"Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients","volume":"7","author":"Zhou","year":"2020","journal-title":"National Science Review"},{"key":"2025100314442381000_9.4.e002285.84","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0311-8"},{"key":"2025100314442381000_9.4.e002285.85","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.stem.2020.09.013","article-title":"SARS-CoV-2 infection of pluripotent stem cell-derived human lung alveolar type 2 cells elicits a rapid Epithelial-Intrinsic inflammatory response","volume":"27","author":"Huang","year":"2020","journal-title":"Cell Stem Cell"},{"key":"2025100314442381000_9.4.e002285.86","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2010722117"},{"key":"2025100314442381000_9.4.e002285.87","doi-asserted-by":"crossref","DOI":"10.1111\/sji.12944","article-title":"Are superantigens the cause of cytokine storm and viral sepsis in severe COVID\u201019? observations and hypothesis","volume":"92","author":"Scaglioni","year":"2020","journal-title":"Scand J Immunol"},{"key":"2025100314442381000_9.4.e002285.88","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0036-4"},{"key":"2025100314442381000_9.4.e002285.89","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117392"},{"key":"2025100314442381000_9.4.e002285.90","doi-asserted-by":"crossref","DOI":"10.1016\/j.lfs.2020.118102","article-title":"Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: lessons from SARS and MERS, and potential therapeutic interventions","volume":"257","author":"Jafarzadeh","year":"2020","journal-title":"Life Sci"},{"key":"2025100314442381000_9.4.e002285.91","doi-asserted-by":"crossref","DOI":"10.1016\/j.lfs.2020.117905","article-title":"Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to macrophage activation syndrome: therapeutic implications","volume":"256","author":"Banu","year":"2020","journal-title":"Life Sci"},{"key":"2025100314442381000_9.4.e002285.92","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.180513"},{"key":"2025100314442381000_9.4.e002285.93","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(02)00271-6"},{"key":"2025100314442381000_9.4.e002285.94","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ijid.2020.03.013","article-title":"Patients of COVID-19 may benefit from sustained Lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression","volume":"95","author":"Liu","year":"2020","journal-title":"Int J of Dis"},{"key":"2025100314442381000_9.4.e002285.95","doi-asserted-by":"crossref","first-page":"762-768","DOI":"10.1093\/cid\/ciaa248","article-title":"Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China","volume":"71","author":"Qin","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2025100314442381000_9.4.e002285.96","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001089"},{"key":"2025100314442381000_9.4.e002285.97","first-page":"PA2110","article-title":"Mi\u0142kowska - Dymanowska J, Piotrowski W, et al. Eosinopenia as a prognostic factor in patients with acute exacerbation of chronic obstructive pulmonary disease","volume":"50","author":"Bialas","year":"2017","journal-title":"European Respiratory Journal"},{"key":"2025100314442381000_9.4.e002285.98","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s12016-015-8526-3","article-title":"The role and immunobiology of eosinophils in the respiratory system: a comprehensive review","volume":"50","author":"Eng","year":"2016","journal-title":"Clin Rev Allergy Immunol"},{"key":"2025100314442381000_9.4.e002285.99","doi-asserted-by":"crossref","unstructured":"Isobe Y , Kato T , Arita M . Emerging roles of eosinophils and eosinophil-derived lipid mediators in the resolution of inflammation. Front Immunol 2012;3.doi:10.3389\/fimmu.2012.00270","DOI":"10.3389\/fimmu.2012.00270"},{"key":"2025100314442381000_9.4.e002285.100","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-020-05991-x"},{"key":"2025100314442381000_9.4.e002285.101","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a016295","article-title":"Il-6 in inflammation, immunity, and disease","volume":"6","author":"Tanaka","year":"2014","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2025100314442381000_9.4.e002285.102","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1159\/000505099","article-title":"Interleukin-6: a Masterplayer in the cytokine network","volume":"98","author":"Uciechowski","year":"2020","journal-title":"Oncology"},{"key":"2025100314442381000_9.4.e002285.103","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2014.05.024"},{"key":"2025100314442381000_9.4.e002285.104","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.20556"},{"key":"2025100314442381000_9.4.e002285.105","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3520-14.2014"},{"key":"2025100314442381000_9.4.e002285.106","first-page":"26059","article-title":"Shedding of endogenous interleukin-6 receptor (IL-6R) is governed by a disintegrin and metalloproteinase (ADAM) proteases while a full-length IL-6R isoform localizes to circulating microvesicles","volume":"290","author":"Schumacher","year":"2015","journal-title":"J of Chem"},{"key":"2025100314442381000_9.4.e002285.107","doi-asserted-by":"crossref","DOI":"10.3390\/cancers11111736","article-title":"Adam17 activity and IL-6 trans-signaling in inflammation and cancer","volume":"11","author":"Schumacher","year":"2019","journal-title":"Cancers"},{"key":"2025100314442381000_9.4.e002285.108","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-017-0300-z"},{"key":"2025100314442381000_9.4.e002285.109","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2018-0028"},{"key":"2025100314442381000_9.4.e002285.110","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1177\/1078155217745144","article-title":"Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade","volume":"25","author":"Stroud","year":"2019","journal-title":"Journal of Oncology Pharmacy Practice"},{"key":"2025100314442381000_9.4.e002285.111","doi-asserted-by":"crossref","first-page":"111694","DOI":"10.1016\/j.fct.2020.111694","article-title":"Tocilizumab improves oxidative stress and endothelial glycocalyx: a mechanism that may explain the effects of biological treatment on COVID-19","volume":"145","author":"Ikonomidis","year":"2020","journal-title":"Food and Chemical Toxicology"},{"key":"2025100314442381000_9.4.e002285.112","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2020.104370"},{"key":"2025100314442381000_9.4.e002285.113","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.annonc.2020.03.296","article-title":"Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China","volume":"31","author":"Zhang","year":"2020","journal-title":"Annals of Oncology"},{"key":"2025100314442381000_9.4.e002285.114","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25801"},{"key":"2025100314442381000_9.4.e002285.115","doi-asserted-by":"crossref","DOI":"10.3390\/medicina56080377","article-title":"Rapid and impressive response to a combined treatment with single-dose tocilizumab and NIV in a patient with COVID-19 Pneumonia\/ARDS","volume":"56","author":"Cascella","year":"2020","journal-title":"Medicina"},{"key":"2025100314442381000_9.4.e002285.116","doi-asserted-by":"crossref","DOI":"10.1186\/s12967-020-02573-9","article-title":"Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial","volume":"18","author":"Perrone","year":"2020","journal-title":"J Transl Med"},{"key":"2025100314442381000_9.4.e002285.117","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Ruiz M , L\u00f3pez-Medrano F , P\u00e9rez-Jacoiste As\u00edn MA , et al . Tocilizumab for the treatment of adult patients with severe COVID-19 pneumonia: a single-center cohort study. J Med Virol 2020.","DOI":"10.1002\/jmv.26308"},{"key":"2025100314442381000_9.4.e002285.118","doi-asserted-by":"crossref","DOI":"10.1016\/j.autrev.2020.102568","article-title":"Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy","volume":"19","author":"Toniati","year":"2020","journal-title":"Autoimmun Rev"},{"key":"2025100314442381000_9.4.e002285.119","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-218122"},{"key":"2025100314442381000_9.4.e002285.120","unstructured":"Regeneron Pharmaceuticals Inc . Regeneron and Sanofi provide update on Kevzara\u00ae (sarilumab) phase 3 US. trial in COVID-19 patients, 2020. Available: https:\/\/newsroom.regeneron.com\/news-releases\/news-release-details\/regeneron-and-sanofi-provide-update-kevzarar-sarilumab-phase-3"},{"key":"2025100314442381000_9.4.e002285.121","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1001\/jamainternmed.2020.6820","article-title":"Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia","volume":"181","author":"Hermine","year":"2021","journal-title":"JAMA Intern Med"},{"key":"2025100314442381000_9.4.e002285.122","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30483-7"},{"key":"2025100314442381000_9.4.e002285.123","doi-asserted-by":"crossref","unstructured":"Salama C , Han J , Yau L , et al . Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia. medRxiv 2020.","DOI":"10.1101\/2020.10.21.20210203"},{"key":"2025100314442381000_9.4.e002285.124","article-title":"Interleukin-6 receptor antagonists in critically ill patients with Covid-19","author":"Gordon","year":"2021","journal-title":"N Engl J Med"},{"key":"2025100314442381000_9.4.e002285.125","unstructured":"Horby PW , Pessoa-Amorim G , Peto L , et al . Tocilizumab in patients admitted to hospital with COVID-19 (recovery): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv 2021."},{"key":"2025100314442381000_9.4.e002285.126","doi-asserted-by":"crossref","DOI":"10.1001\/jamainternmed.2020.6252","article-title":"Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19","volume":"181","author":"Gupta","year":"2021","journal-title":"JAMA Intern Med"},{"key":"2025100314442381000_9.4.e002285.127","doi-asserted-by":"crossref","unstructured":"Rosas I , Br\u00e4u N , Waters M , et al . Tocilizumab in hospitalized patients with COVID-19 pneumonia. medRxiv 2020.","DOI":"10.1101\/2020.08.27.20183442"},{"key":"2025100314442381000_9.4.e002285.128","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028836"},{"key":"2025100314442381000_9.4.e002285.129","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n84"},{"key":"2025100314442381000_9.4.e002285.130","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1002\/jmv.26509","article-title":"Efficacy of tocilizumab in COVID-19: a systematic review and meta-analysis","volume":"93","author":"Aziz","year":"2021","journal-title":"J Med Virol"},{"key":"2025100314442381000_9.4.e002285.131","doi-asserted-by":"crossref","unstructured":"Malgie J , Schoones JW , Pijls BG . Decreased mortality in coronavirus disease 2019 patients treated with tocilizumab: a rapid systematic review and meta-analysis of observational studies. Clinical Infectious Diseases 2020;20.doi:10.1093\/cid\/ciaa1445","DOI":"10.1093\/cid\/ciaa1445"},{"key":"2025100314442381000_9.4.e002285.132","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cmi.2020.10.036","article-title":"Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis","volume":"27","author":"Tleyjeh","year":"2021","journal-title":"Clinical Microbiology and Infection"},{"key":"2025100314442381000_9.4.e002285.133","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2007764"},{"key":"2025100314442381000_9.4.e002285.134","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m3379"},{"key":"2025100314442381000_9.4.e002285.135","unstructured":"B A , RL M , AH S VL . Infectious diseases Society of America guidelines on the treatment and management of patients with COVID-19: IDSA, 2021. Available: https:\/\/www.idsociety.org\/practice-guideline\/covid-19-guideline-treatment-and-management\/#toc-8"},{"key":"2025100314442381000_9.4.e002285.136","first-page":"693","article-title":"Dexamethasone in hospitalized patients with Covid-19 - preliminary report","volume":"384","author":"Horby","year":"2020","journal-title":"N Engl J Med"},{"key":"2025100314442381000_9.4.e002285.137","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1001\/jamainternmed.2020.6615","article-title":"Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial","volume":"181","author":"Salvarani","year":"2021","journal-title":"JAMA Intern Med"},{"key":"2025100314442381000_9.4.e002285.138","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-218479"},{"key":"2025100314442381000_9.4.e002285.139","article-title":"Early combination of tocilizumab and corticosteroids: an upgrade in anti-inflammatory therapy for severe COVID","author":"Mart\u00ednez-Urbistondo","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2025100314442381000_9.4.e002285.140","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1111\/apt.15777","article-title":"Editorial: low population mortality from COVID-19 in countries South of latitude 35 degrees North supports vitamin D as a factor determining severity","volume":"51","author":"Rhodes","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"key":"2025100314442381000_9.4.e002285.141","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2020.198018"},{"key":"2025100314442381000_9.4.e002285.142","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1053\/j.gastro.2020.06.048","article-title":"Alterations in fecal fungal microbiome of patients with COVID-19 during time of hospitalization until discharge","volume":"159","author":"Zuo","year":"2020","journal-title":"Gastroenterology"},{"key":"2025100314442381000_9.4.e002285.143","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-322294"},{"key":"2025100314442381000_9.4.e002285.144","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.55"},{"key":"2025100314442381000_9.4.e002285.145","doi-asserted-by":"crossref","first-page":"14430","DOI":"10.1038\/s41598-018-32860-x","article-title":"Regulation of the effector function of CD8","volume":"8","author":"Luu","year":"2018","journal-title":"Sci Rep"},{"key":"2025100314442381000_9.4.e002285.146","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1093\/eurpub\/ckaa150","article-title":"COVID-19 mortality: a complex interplay of sex, gender and ethnicity","volume":"30","author":"Islam","year":"2020","journal-title":"Eur J Public Health"},{"key":"2025100314442381000_9.4.e002285.147","unstructured":"B A , RL M , AH S VL , et al . Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19: IDSA, 2021. Available: https:\/\/www.idsociety.org\/practice-guideline\/covid-19-guideline-treatment-and-management\/#toc-8"},{"key":"2025100314442381000_9.4.e002285.148","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3153"},{"key":"2025100314442381000_9.4.e002285.149","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.ijid.2020.07.078","article-title":"Low-Dose subcutaneous tocilizumab to prevent disease progression in patients with moderate COVID-19 pneumonia and hyperinflammation","volume":"100","author":"Potere","year":"2020","journal-title":"Int J of Dis"},{"key":"2025100314442381000_9.4.e002285.150","doi-asserted-by":"crossref","unstructured":"Busani S , Bedini A , Biagioni E , et al . Two fatal cases of acute liver failure due to HSV-1 infection in COVID-19 patients following immunomodulatory therapies. Clin Infect Dis 2020.doi:10.1093\/cid\/ciaa1246","DOI":"10.1093\/cid\/ciaa1246"},{"key":"2025100314442381000_9.4.e002285.151","doi-asserted-by":"crossref","first-page":"e474","DOI":"10.1016\/S2665-9913(20)30173-9","article-title":"Tocilizumab in patients with severe COVID-19: a retrospective cohort study","volume":"2","author":"Guaraldi","year":"2020","journal-title":"Lancet Rheumatol"},{"key":"2025100314442381000_9.4.e002285.152","doi-asserted-by":"crossref","unstructured":"Somers EC , Eschenauer GA , Troost JP , et al . Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis 2020;382.doi:10.1093\/cid\/ciaa954","DOI":"10.1093\/cid\/ciaa954"},{"key":"2025100314442381000_9.4.e002285.153","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-000930","article-title":"The Society for immunotherapy of cancer perspective on regulation of interleukin-6 signaling in COVID-19-related systemic inflammatory response","volume":"8","author":"Arnaldez","year":"2020","journal-title":"Journal for ImmunoTherapy of Cancer"},{"key":"2025100314442381000_9.4.e002285.154","unstructured":"Roivant announces development of anti-gm-csf monoclonal antibody to prevent and treat acute respiratory distress syndrome (ARDS) in patients with COVID-19 - Roivant Sciences, 2020. Available: https:\/\/roivant.com\/roivant-announces-development-of-anti-gm-csf-monoclonal-antibody-to-prevent-and-treat-acute-respiratory-distress-syndrome-ards-in-patients-with-covid-19.html"},{"key":"2025100314442381000_9.4.e002285.155","doi-asserted-by":"crossref","first-page":"e393","DOI":"10.1016\/S2665-9913(20)30164-8","article-title":"Anakinra for severe forms of COVID-19: a cohort study","volume":"2","author":"Huet","year":"2020","journal-title":"The Lancet Rheumatology"},{"key":"2025100314442381000_9.4.e002285.156","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaut.2020.102537","article-title":"High dose subcutaneous Anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill COVID-19 patients","volume":"115","author":"Iglesias-Juli\u00e1n","year":"2020","journal-title":"J Autoimmun"},{"key":"2025100314442381000_9.4.e002285.157","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s15010-020-01476-7","article-title":"Baricitinib as rescue therapy in a patient with COVID-19 with no complete response to sarilumab","volume":"48","author":"Cingolani","year":"2020","journal-title":"Infection"},{"key":"2025100314442381000_9.4.e002285.158","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1056\/NEJMoa2031994","article-title":"Baricitinib plus Remdesivir for hospitalized adults with Covid-19","volume":"384","author":"Kalil","year":"2021","journal-title":"N Engl J Med"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2020-002285","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T21:46:21Z","timestamp":1759527981000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2020-002285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4]]},"references-count":158,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,9]]},"published-print":{"date-parts":[[2021,4]]}},"alternative-id":["10.1136\/jitc-2020-002285"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2020-002285","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4]]}}}