Efficacy of tocilizumab in patients with COVID-19 ARDS undergoing noninvasive ventilation

DOI record: { "DOI": "10.1186/s13054-020-03306-6", "ISSN": [ "1364-8535" ], "URL": "http://dx.doi.org/10.1186/s13054-020-03306-6", "abstract": "<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely variable, ranging from asymptomatic patients to those who develop severe acute respiratory distress syndrome (ARDS). As for now, there are still no really effective therapies for coronavirus disease 2019 (COVID-19). Some evidences suggest that tocilizumab (TCZ) may avoid the progression of severe COVID-19. The aim of this retrospective case-control study was to analyze the efficacy and safety of TCZ in patients with COVID-19 ARDS undergoing noninvasive mechanical ventilation (NIV).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Seventy-nine consecutive patients with severe COVID-19 pneumonia and worsening acute respiratory failure (ARF) were admitted to the Pulmonology Unit of Azienda USL of Reggio Emilia-IRCCS. All patients were inflamed (elevated CRP and IL-6 levels) and received NIV at admission according to the presence of a pO<jats:sub>2</jats:sub>/FiO<jats:sub>2</jats:sub>ratio ≤ 200 mmHg. The possibility of being treated with TCZ depended on the drug availability. The primary outcome was the in-hospital mortality rate. A secondary composite outcome of worsening was represented by the patients who died in the pulmonology unit or were intubated.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Out of 79 patients, 41 were treated with TCZ. Twenty-eight patients received intravenous (IV) TCZ and 13 patients received subcutaneous (SC) TCZ. In-hospital overall mortality rate was 38% (30/79 patients). The probabilities of dying and being intubated during the follow-up using Kaplan-Meier method were significantly lower in total patients treated with TCZ compared to those of patients not treated with TCZ (log-rank<jats:italic>p</jats:italic>value = 0.006 and 0.036, respectively). However, using Cox multivariate analyses adjusted for age and Charlson comorbidity index only the association with the reduced risk of being intubated or dying maintained the significance (HR 0.44, 95%CI 0.22–0.89,<jats:italic>p</jats:italic> = 0.022). Two patients treated with TCZ developed cavitating lung lesions during the follow-up.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>This study shows that TCZ treatment may be effective in COVID-19 patients with severe respiratory impairment receiving NIV. More data on safety are required. Randomized controlled trials are needed to confirm these results.</jats:p></jats:sec>", "alternative-id": [ "3306" ], "article-number": "589", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "12 July 2020" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "22 September 2020" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "29 September 2020" }, { "group": { "label": "Ethics approval and consent to participate", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "This study was approved by the Local Ethics Committee of Area Vasta Emilia Nord (no. 2020/0045199)." }, { "group": { "label": "Consent for publication", "name": "EthicsHeading" }, "name": "Ethics", "order": 2, "value": "Since not all patients were able to give their informed consent, the Ethics Committee waived this requirement. Informed consent was sought from all surviving patients as soon as they regained their mental competence." }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 3, "value": "The authors declare that there are no conflicts of interest regarding the publication of this article." } ], "author": [ { "ORCID": "https://orcid.org/0000-0003-3950-5789", "affiliation": [], "authenticated-orcid": false, "family": "Menzella", "given": "Francesco", "sequence": "first" }, { "affiliation": [], "family": "Fontana", "given": "Matteo", "sequence": "additional" }, { "affiliation": [], "family": "Salvarani", "given": "Carlo", "sequence": "additional" }, { "affiliation": [], "family": "Massari", "given": "Marco", "sequence": "additional" }, { "affiliation": [], "family": "Ruggiero", "given": "Patrizia", "sequence": "additional" }, { "affiliation": [], "family": "Scelfo", "given": "Chiara", "sequence": "additional" }, { "affiliation": [], "family": "Barbieri", "given": "Chiara", "sequence": "additional" }, { "affiliation": [], "family": "Castagnetti", "given": "Claudia", "sequence": "additional" }, { "affiliation": [], "family": "Catellani", "given": "Chiara", "sequence": "additional" }, { "affiliation": [], "family": "Gibellini", "given": "Giorgia", "sequence": "additional" }, { "affiliation": [], "family": "Falco", "given": "Francesco", "sequence": "additional" }, { "affiliation": [], "family": "Ghidoni", "given": "Giulia", "sequence": "additional" }, { "affiliation": [], "family": "Livrieri", "given": "Francesco", "sequence": "additional" }, { "affiliation": [], "family": "Montanari", "given": "Gloria", "sequence": "additional" }, { "affiliation": [], "family": "Casalini", "given": "Eleonora", "sequence": "additional" }, { "affiliation": [], "family": "Piro", "given": "Roberto", "sequence": "additional" }, { "affiliation": [], "family": "Mancuso", "given": "Pamela", "sequence": "additional" }, { "affiliation": [], "family": "Ghidorsi", "given": "Luca", "sequence": "additional" }, { "affiliation": [], "family": "Facciolongo", "given": "Nicola", "sequence": "additional" } ], "container-title": "Critical Care", "container-title-short": "Crit Care", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2020, 9, 29 ] ], "date-time": "2020-09-29T14:04:04Z", "timestamp": 1601388244000 }, "deposited": { "date-parts": [ [ 2023, 10, 24 ] ], "date-time": "2023-10-24T23:47:36Z", "timestamp": 1698191256000 }, "indexed": { "date-parts": [ [ 2025, 6, 7 ] ], "date-time": "2025-06-07T16:28:34Z", "timestamp": 1749313714541, "version": "3.37.3" }, "is-referenced-by-count": 49, "issue": "1", "issued": { "date-parts": [ [ 2020, 9, 29 ] ] }, "journal-issue": { "issue": "1", "published-print": { "date-parts": [ [ 2020, 12 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2020, 9, 29 ] ], "date-time": "2020-09-29T00:00:00Z", "timestamp": 1601337600000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2020, 9, 29 ] ], "date-time": "2020-09-29T00:00:00Z", "timestamp": 1601337600000 } } ], "link": [ { "URL": "https://link.springer.com/content/pdf/10.1186/s13054-020-03306-6.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/article/10.1186/s13054-020-03306-6/fulltext.html", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://link.springer.com/content/pdf/10.1186/s13054-020-03306-6.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1186", "published": { "date-parts": [ [ 2020, 9, 29 ] ] }, "published-online": { "date-parts": [ [ 2020, 9, 29 ] ] }, "published-print": { "date-parts": [ [ 2020, 12 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1186/s13054-020-02911-9", "author": "X Li", "doi-asserted-by": "publisher", "first-page": "198", "journal-title": "Crit Care", "key": "3306_CR1", "unstructured": "Li X, Ma X. Acute respiratory failure in COVID-19: is it \"typical\" ARDS? Crit Care. 2020;24:198.", "volume": "24", "year": "2020" }, { "DOI": "10.1016/S0140-6736(20)30183-5", "author": "C Huang", "doi-asserted-by": "publisher", "first-page": "497", "journal-title": "Lancet", "key": "3306_CR2", "unstructured": "Huang C, Wang Y, Li X, Ren L, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.", "volume": "395", "year": "2020" }, { "DOI": "10.1016/j.cytogfr.2020.04.002", "doi-asserted-by": "crossref", "key": "3306_CR3", "unstructured": "Sun X, Wang T, Cai D, Zhiwei Hu, Jin'an Chen, Hui Liao, et al. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev. 2020;53:38-42." }, { "DOI": "10.1111/j.1440-1843.2006.00942.x", "author": "JY Chien", "doi-asserted-by": "publisher", "first-page": "715", "journal-title": "Respirology", "key": "3306_CR4", "unstructured": "Chien JY, Hsueh PR, Cheng WC, Yu CJ, Yang PC. Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology. 2006;11:715–22.", "volume": "11", "year": "2006" }, { "DOI": "10.1038/srep25359", "author": "CK Min", "doi-asserted-by": "publisher", "first-page": "25359", "journal-title": "Sci Rep", "key": "3306_CR5", "unstructured": "Min CK, Cheon S, Ha NY, Sohn KM, Kim Y, Aigerim A, et al. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep. 2016;6:25359.", "volume": "6", "year": "2016" }, { "DOI": "10.1016/j.jaci.2020.05.008", "author": "T Herold", "doi-asserted-by": "publisher", "first-page": "128", "journal-title": "J Allergy Clin Immunol", "key": "3306_CR6", "unstructured": "Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, Bergwelt-Baildon MV, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020;146:128–36.", "volume": "146", "year": "2020" }, { "DOI": "10.1002/jmv.25948", "doi-asserted-by": "publisher", "key": "3306_CR7", "unstructured": "Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: a meta-analysis. J Med Virol. 2020. https://doi.org/10.1002/jmv.25948." }, { "DOI": "10.1056/NEJMoa2021436", "doi-asserted-by": "publisher", "key": "3306_CR8", "unstructured": "RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2021436." }, { "DOI": "10.1073/pnas.2005615117", "author": "X Xu", "doi-asserted-by": "publisher", "first-page": "10970", "journal-title": "Proc Natl Acad Sci U S A", "key": "3306_CR9", "unstructured": "Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117:10970–5.", "volume": "117", "year": "2020" }, { "DOI": "10.1016/j.autrev.2020.102568", "author": "P Toniati", "doi-asserted-by": "publisher", "first-page": "102568", "issue": "7", "journal-title": "Autoimmun Rev", "key": "3306_CR10", "unstructured": "Toniati P, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, et al. 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. Autoimmun Rev. 2020;19(7):102568.", "volume": "19", "year": "2020" }, { "key": "3306_CR11", "unstructured": "Sciascia S, Aprà F, Baffa A, Baldovino S, Boaro D, Boero R, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol. 2020;38(3):529-532." }, { "key": "3306_CR12", "unstructured": "Price CC, Altice FL, Shyr Y, Koff A, Pischel L, Goshua G, et al. Tocilizumab treatment for cytokine release syndrome in hospitalized COVID-19 patients: survival and clinical outcomes. Chest. 2020; S0012-3692(20)31670-6." }, { "DOI": "10.1016/S2665-9913(20)30173-9", "doi-asserted-by": "publisher", "key": "3306_CR13", "unstructured": "Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. 2020; https://doi.org/10.1016/S2665-9913(20)30173-9." }, { "DOI": "10.1183/13993003.02426-2016", "author": "B Rochwerg", "doi-asserted-by": "publisher", "first-page": "1602426", "issue": "2", "journal-title": "Eur Respir J", "key": "3306_CR14", "unstructured": "Rochwerg B, Brochard L, Elliott MW, Hess D, Hill NS, Nava S, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J. 2017;50(2):1602426.", "volume": "50", "year": "2017" }, { "DOI": "10.5414/CP201819", "author": "X Zhang", "doi-asserted-by": "publisher", "first-page": "443", "issue": "6", "journal-title": "Int J Clin Pharmacol Ther", "key": "3306_CR15", "unstructured": "Zhang X, Georgy A, Rowell L. Pharmacokinetics and pharmacodynamics of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, following single-dose administration by subcutaneous and intravenous routes to healthy subjects. Int J Clin Pharmacol Ther. 2013;51(6):443–55.", "volume": "51", "year": "2013" }, { "DOI": "10.1007/s40262-012-0027-4", "author": "M Dostalek", "doi-asserted-by": "publisher", "first-page": "83", "journal-title": "Clin Pharmacokinet", "key": "3306_CR16", "unstructured": "Dostalek M, Gardner I, Gurbaxani BM, Rose RH, Chetty M. Pharmacokinetics, pharmacodynamics and physiologically-based pharmacokinetic modelling of monoclonal antibodies. Clin Pharmacokinet. 2013;52:83–124.", "volume": "52", "year": "2013" }, { "DOI": "10.1016/S1441-2772(23)00387-3", "doi-asserted-by": "crossref", "key": "3306_CR17", "unstructured": "Zangrillo A, Beretta L, Scandroglio AM, Monti G, Forminskiy E, Colombo S, et al. Characteristics, treatment, outcomes and cause of death of invasively ventilated patients with COVID-19 ARDS in Milan, Italy. Crit Care Resusc. 2020. [Epub ahead of print]." }, { "DOI": "10.1136/bmj.m1966", "author": "M Petrilli", "doi-asserted-by": "publisher", "first-page": "m1966", "journal-title": "BMJ", "key": "3306_CR18", "unstructured": "Petrilli M, Jones SA, Yang J, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020;369:m1966.", "volume": "369", "year": "2020" }, { "DOI": "10.1002/jmv.26137", "doi-asserted-by": "publisher", "key": "3306_CR19", "unstructured": "Qin L, Li X, Shi J, et al. Gendered effects on inflammation reaction and outcome of COVID-19 patients in Wuhan. J Med Virol. 2020. https://doi.org/10.1002/jmv.26137." }, { "DOI": "10.1080/14712598.2020.1770222", "author": "MA González-Gay", "doi-asserted-by": "publisher", "first-page": "717", "journal-title": "Expert Opin Biol Ther", "key": "3306_CR20", "unstructured": "González-Gay MA, Mayo J, Castañeda S, Cifrián JM, Hernández-Rodríguez J. Tocilizumab: from the rheumatology practice to the fight against COVID-19, a virus infection with multiple faces. Expert Opin Biol Ther. 2020;20:717–23.", "volume": "20", "year": "2020" }, { "DOI": "10.1016/j.ejim.2020.05.021", "author": "C Campochiaro", "doi-asserted-by": "publisher", "first-page": "43", "journal-title": "Eur J Intern Med", "key": "3306_CR21", "unstructured": "Campochiaro C, Della-Torre E, Cavalli G, De Luca G, Ripa M, Boffini N, et al. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med. 2020;76:43–9.", "volume": "76", "year": "2020" }, { "DOI": "10.1016/j.ijantimicag.2020.106103", "author": "SH Lan", "doi-asserted-by": "publisher", "first-page": "106103", "journal-title": "Int J Antimicrob Agents", "key": "3306_CR22", "unstructured": "Lan SH, Lai CC, Huang HT, Chang SP, Lu LC, Hsueh PR. Tocilizumab for severe COVID-19: a systematic review and meta-analysis. Int J Antimicrob Agents. 2020;23:106103 https://doi.org/10.1016/j.ijantimicag.2020.106103.", "volume": "23", "year": "2020" }, { "DOI": "10.1093/cid/ciaa954", "doi-asserted-by": "publisher", "key": "3306_CR23", "unstructured": "Somers EC, Eschenauer GA, Troost JP, Golob JL, Gandhi TN, Wang L, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis. 2020:ciaa954 https://doi.org/10.1093/cid/ciaa954." }, { "DOI": "10.1136/annrheumdis-2020-218479", "doi-asserted-by": "publisher", "key": "3306_CR24", "unstructured": "Ramiro S, Mostard RLM, Magro-Checa C, van Dongen CMP, Dormans T, Buijs J, et al. Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study. Ann Rheum Dis. 2020:annrheumdis-2020-218479. https://doi.org/10.1136/annrheumdis-2020-218479." }, { "DOI": "10.1016/j.jcv.2020.104415", "author": "P Giorgi Rossi", "doi-asserted-by": "publisher", "first-page": "104415", "journal-title": "J Clin Virol", "key": "3306_CR25", "unstructured": "Giorgi Rossi P, Emilia-Romagna COVID-19 working group, Broccoli S, Angelini P. Case fatality rate in patients with COVID-19 infection and its relationship with length of follow up. J Clin Virol. 2020;128:104415.", "volume": "128", "year": "2020" } ], "reference-count": 25, "references-count": 25, "relation": {}, "resource": { "primary": { "URL": "https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-03306-6" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Efficacy of tocilizumab in patients with COVID-19 ARDS undergoing noninvasive ventilation", "type": "journal-article", "update-policy": "https://doi.org/10.1007/springer_crossmark_policy", "volume": "24" }