Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19

DOI record: { "DOI": "10.1093/cid/ciaa954", "ISSN": [ "1058-4838", "1537-6591" ], "URL": "http://dx.doi.org/10.1093/cid/ciaa954", "abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>Severe coronavirus disease 2019 (COVID-19) can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers, consistent with cytokine release syndrome for which IL-6 blockade is an approved treatment.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability postintubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared with tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability of treatment weighting (IPTW).</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range, 28–67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean: 55 vs 60 years), less likely to have chronic pulmonary disease (10% vs 28%), and had lower D-dimer values at time of intubation (median: 2.4 vs 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR, .55; 95% CI, .33–.90) and improved status on the ordinal outcome scale [OR per 1-level increase, .58; .36–.94). Although tocilizumab was associated with an increased proportion of patients with superinfections (54% vs 26%; P &amp;lt; .001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection (22% vs 15%; P = .42). Staphylococcus aureus accounted for ~50% of bacterial pneumonia.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with lower mortality despite higher superinfection occurrence.</jats:p>\n </jats:sec>", "author": [ { "ORCID": "https://orcid.org/0000-0001-5234-3978", "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" }, { "name": "Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA" }, { "name": "Department of Obstetrics & Gynecology, University of Michigan, Ann Arbor, Michigan, USA" } ], "authenticated-orcid": false, "family": "Somers", "given": "Emily C", "sequence": "first" }, { "affiliation": [ { "name": "Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Eschenauer", "given": "Gregory A", "sequence": "additional" }, { "affiliation": [ { "name": "Michigan Institute for Clinical & Health Research, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Troost", "given": "Jonathan P", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Golob", "given": "Jonathan L", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Gandhi", "given": "Tejal N", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Wang", "given": "Lu", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Zhou", "given": "Nina", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Petty", "given": "Lindsay A", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Baang", "given": "Ji Hoon", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Pharmacy, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Dillman", "given": "Nicholas O", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Frame", "given": "David", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Gregg", "given": "Kevin S", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Kaul", "given": "Dan R", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Pharmacy, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Nagel", "given": "Jerod", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Pharmacy, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Patel", "given": "Twisha S", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Zhou", "given": "Shiwei", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Lauring", "given": "Adam S", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Learning Health Sciences, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Hanauer", "given": "David A", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Martin", "given": "Emily", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Sharma", "given": "Pratima", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Emergency Medicine, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Fung", "given": "Christopher M", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA" } ], "family": "Pogue", "given": "Jason M", "sequence": "additional" } ], "container-title": "Clinical Infectious Diseases", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2020, 7, 10 ] 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patients from Wuhan, China", "author": "Ruan", "doi-asserted-by": "crossref", "first-page": "846", "journal-title": "Intens Care Med", "key": "2021071519590476100_CIT0003", "volume": "46", "year": "2020" }, { "DOI": "10.1126/science.abb8925", "article-title": "Cytokine release syndrome in severe COVID-19", "author": "Moore", "doi-asserted-by": "crossref", "first-page": "473", "journal-title": "Science", "key": "2021071519590476100_CIT0004", "volume": "368", "year": "2020" }, { "DOI": "10.1016/S0140-6736(20)30628-0", "article-title": "COVID-19: consider cytokine storm syndromes and immunosuppression", "author": "Mehta", "doi-asserted-by": "crossref", "first-page": "1033", "journal-title": "Lancet", "key": "2021071519590476100_CIT0005", "volume": "395", "year": "2020" }, { "DOI": "10.1136/bmj.m1966", "article-title": "Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study", "author": "Petrilli", "doi-asserted-by": "crossref", "first-page": "m1966", "journal-title": "BMJ", "key": "2021071519590476100_CIT0006", "volume": "369", "year": "2020" }, { "DOI": "10.1016/S2665-9913(20)30120-X", "article-title": "The immunology of COVID-19: is immune modulation an option for treatment?", "author": "Zhong", "doi-asserted-by": "crossref", "first-page": "e428", "journal-title": "Lancet Rheumatol", "key": "2021071519590476100_CIT0007", "volume": "2", "year": "2020" }, { "DOI": "10.1182/blood-2013-02-485623", "article-title": "Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy", "author": "Teachey", "doi-asserted-by": "crossref", "first-page": "5154", "journal-title": "Blood", "key": "2021071519590476100_CIT0008", "volume": "121", "year": "2013" }, { "DOI": "10.1073/pnas.2005615117", "article-title": "Effective treatment of severe COVID-19 patients with tocilizumab", "author": "Xu", "doi-asserted-by": "crossref", "first-page": "10970", "journal-title": "Proc Natl Acad Sci", "key": "2021071519590476100_CIT0009", "volume": "117", "year": "2020" }, { "article-title": "Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19", "author": "Sciascia", "first-page": "529", "journal-title": "Clin Exp Rheumatol", "key": "2021071519590476100_CIT0010", "volume": "38", "year": "2020" }, { "DOI": "10.1002/jmv.25801", "article-title": "Tocilizumab treatment in COVID-19: a single center experience", "author": "Luo", "doi-asserted-by": "crossref", "first-page": "814", "journal-title": "J Med Virol", "key": "2021071519590476100_CIT0011", "volume": "92", "year": "2020" }, { "DOI": "10.1016/j.ejim.2020.05.009", "article-title": "Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia", "author": "Capra", "doi-asserted-by": "crossref", "first-page": "31", "journal-title": "Eur J Intern Med", "key": "2021071519590476100_CIT0012", "volume": "76", "year": "2020" }, { "DOI": "10.1016/j.medmal.2020.05.001", "article-title": "Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients", "author": "Klopfenstein", "doi-asserted-by": "crossref", "first-page": "397", "journal-title": "Médecine Mal Infect", "key": "2021071519590476100_CIT0013", "volume": "50", "year": "2020" }, { "article-title": "Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory suppo", "author": "Gritti", "key": "2021071519590476100_CIT0014", "year": "2020." }, { "DOI": "10.1016/j.chest.2020.04.024", "article-title": "Use of tocilizumab for COVID-19-induced cytokine release syndrome: a cautionary case report", "author": "Radbel", "doi-asserted-by": "crossref", "first-page": "e15", "journal-title": "Chest", "key": "2021071519590476100_CIT0015", "volume": "158", "year": "2020" }, { "DOI": "10.1016/j.autrev.2020.102564", "article-title": "Tocilizumab for cytokine storm syndrome in COVID-19 pneumonia: an increased risk for candidemia?", "author": "Antinori", "doi-asserted-by": "crossref", "first-page": "102564", "journal-title": "Autoimmun Rev", "key": "2021071519590476100_CIT0016", "volume": "19", "year": "2020" }, { "DOI": "10.1016/S1473-3099(13)70327-X", "article-title": "Open source clinical science for emerging infections", "author": "Dunning", "doi-asserted-by": "crossref", "first-page": "8", "journal-title": "Lancet Infect Dis", "key": "2021071519590476100_CIT0017", "volume": "14", "year": "2014" }, { "article-title": "Global outbreak research: harmony not hegemony", "author": "ISARIC Clinical Characterization Group", "first-page": "30440", "journal-title": "Lancet Infect Dis", "key": "2021071519590476100_CIT0018", "volume": "3099", "year": "2020" }, { "DOI": "10.1097/EDE.0b013e3181577511", "article-title": "Strengthening The Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration", "author": "Vandenbroucke", "doi-asserted-by": "crossref", "first-page": "805", "journal-title": "Epidemiology", "key": "2021071519590476100_CIT0019", "volume": "18", "year": "2007" }, { "DOI": "10.1093/aje/kwm324", "article-title": "Immortal time bias in pharmaco-epidemiology", "author": "Suissa", "doi-asserted-by": "crossref", "first-page": "492", "journal-title": "Am J Epidemiol", "key": "2021071519590476100_CIT0020", "volume": "167", "year": "2008" }, { "DOI": "10.1378/chest.07-0617", "article-title": "Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS", "author": "Rice", "doi-asserted-by": "crossref", "first-page": "410", "journal-title": "Chest", "key": "2021071519590476100_CIT0021", "volume": "132", "year": "2007" }, { "DOI": "10.1177/0962280206074463", "article-title": "Multiple imputation of discrete and continuous data by fully conditional specification", "author": "van Buuren", "doi-asserted-by": "crossref", "first-page": "219", "journal-title": "Stat Methods Med Res", "key": "2021071519590476100_CIT0022", "volume": "16", "year": "2007" }, { "DOI": "10.1016/0270-0255(86)90088-6", "article-title": "A new approach to causal inference in mortality studies with a sustained exposure period—application to control of the healthy worker survivor effect", "author": "Robins", "doi-asserted-by": "crossref", "first-page": "1393", "journal-title": "Math Model", "key": "2021071519590476100_CIT0023", "volume": "7", "year": "1986" }, { "DOI": "10.1016/j.ijrobp.2012.02.015", "article-title": "Propensity score-based comparison of long-term outcomes with 3-dimensional conformal radiotherapy vs intensity-modulated radiotherapy for esophageal cancer", "author": "Lin", "doi-asserted-by": "crossref", "first-page": "1078", "journal-title": "Int J Radiat Oncol", "key": "2021071519590476100_CIT0024", "volume": "84", "year": "2012" }, { "DOI": "10.1002/sim.6607", "article-title": "Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies", "author": "Austin", "doi-asserted-by": "crossref", "first-page": "3661", "journal-title": "Stat Med", "key": "2021071519590476100_CIT0025", "volume": "34", "year": "2015" }, { "DOI": "10.1016/j.autrev.2020.102537", "article-title": "The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease", "author": "McGonagle", "doi-asserted-by": "crossref", "first-page": "102537", "journal-title": "Autoimmun Rev", "key": "2021071519590476100_CIT0026", "volume": "19", "year": "2020" }, { "DOI": "10.1161/HYPERTENSIONAHA.118.12286", "article-title": "Novel role of T cells and IL-6 (interleukin-6) in angiotensin II-induced microvascular dysfunction", "author": "Senchenkova", "doi-asserted-by": "crossref", "first-page": "829", "journal-title": "Hypertension", "key": "2021071519590476100_CIT0027", "volume": "73", "year": "2019" }, { "DOI": "10.1038/srep32188", "article-title": "Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity", "author": "Bester", "doi-asserted-by": "crossref", "first-page": "32188", "journal-title": "Sci Rep", "key": "2021071519590476100_CIT0028", "volume": "6", "year": "2016" }, { "DOI": "10.3389/fmicb.2019.01057", "article-title": "The role of interleukin", "author": "Velazquez-Salinas", "doi-asserted-by": "crossref", "first-page": "1057", "journal-title": "Front Microbiol", "key": "2021071519590476100_CIT0029", "volume": "10", "year": "2019" }, { "DOI": "10.1038/srep43829", "article-title": "IL-6 ameliorates acute lung injury in influenza virus infection", "author": "Yang", "doi-asserted-by": "crossref", "first-page": "43829", "journal-title": "Sci Rep", "key": "2021071519590476100_CIT0030", "volume": "7", "year": "2017" } ], "reference-count": 30, "references-count": 30, "relation": { "has-preprint": [ { "asserted-by": "object", 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