Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study
Noa Biran, Andrew Ip, Jaeil Ahn, Ronaldo C Go, Shuqi Wang, Shivam Mathura, Brittany A Sinclaire, Urszula Bednarz, Michael Marafelias, Eric Hansen, David S Siegel, Andre H Goy, Andrew L Pecora, Ihor S Sawczuk, Lauren S Koniaris, Micky Simwenyi, Daniel W Varga, Lisa K Tank, Aaron A Stein, Valerie Allusson, George S Lin, William F Oser, Roman A Tuma, Joseph Reichman, Louis Brusco Jr, Kim L Carpenter, Eric J Costanzo, Vincent Vivona, Stuart L Goldberg, Noa Biran, Andrew Ip, Jaeil Ahn, Ronaldo C Go, Shuqi Wang, Shivam Mathura, Brittany A Sinclaire, Urszula Bednarz, Michael Marafelias, Eric Hansen, David S Siegel, Andre H Goy, Andrew L Pecora, Ihor S Sawczuk, Lauren S Koniaris, Micky Simwenyi, Daniel W Varga, Lisa K Tank, Aaron A Stein, Valerie Allusson, George S Lin, William F Oser, Roman A Tuma, Joseph Reichman, Louis Brusco Jr, Kim L Carpenter, Eric J Costanzo, Vincent Vivona, Stuart L Goldberg
Abstract
Background: Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been proposed to mitigate the cytokine storm syndrome associated with severe COVID-19. We aimed to investigate the association between tocilizumab exposure and hospital-related mortality among patients requiring intensive care unit (ICU) support for COVID-19.
Methods: We did a retrospective observational cohort study at 13 hospitals within the Hackensack Meridian Health network (NJ, USA). We included patients (aged ≥18 years) with laboratory-confirmed COVID-19 who needed support in the ICU. We obtained data from a prospective observational database and compared outcomes in patients who received tocilizumab with those who did not. We applied a multivariable Cox model with propensity score matching to reduce confounding effects. The primary endpoint was hospital-related mortality. The prospective observational database is registered on ClinicalTrials.gov, NCT04347993.
Findings: Between March 1 and April 22, 2020, 764 patients with COVID-19 required support in the ICU, of whom 210 (27%) received tocilizumab. Factors associated with receiving tocilizumab were patients' age, gender, renal function, and treatment location. 630 patients were included in the propensity score-matched population, of whom 210 received tocilizumab and 420 did not receive tocilizumab. 358 (57%) of 630 patients died, 102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. Overall median survival from time of admission was not reached (95% CI 23 days-not reached) among patients receiving tocilizumab and was 19 days (16-26) for those who did not receive tocilizumab (hazard ratio [HR] 0·71, 95% CI 0·56-0·89; p=0·0027). In the primary multivariable Cox regression analysis with propensity matching, an association was noted between receiving tocilizumab and decreased hospital-related mortality (HR 0·64, 95% CI 0·47-0·87; p=0·0040). Similar associations with tocilizumab were noted among subgroups requiring mechanical ventilatory support and with baseline C-reactive protein of 15 mg/dL or higher.
Interpretation: In this observational study, patients with COVID-19 requiring ICU support who received tocilizumab had reduced mortality. Results of ongoing randomised controlled trials are awaited.
Funding: None.
© 2020 Elsevier Ltd. All rights reserved.
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References
- Johns Hopkins University of Medicine COVID-19 dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) Aug 13, 2020.
- Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55
- Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017;39:529–539.
- Le RQ, Li L, Yuan W. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23:943–947.
- Xu Z, Shi L, Wang Y. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–422.
- Xu X, Han M, Li T. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA. 2020;117:10970–10975.
- Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: a single center experience. J Med Virol. 2020;92:814–818.
- Campochiaro C, Della-Torre E, Cavalli G. Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med. 2020;76:43–49.
- Morena V, Milazzo L, Oreni L. Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy. Eur J Intern Med. 2020;76:36–42.
- Toniati P, Piva S, Cattalini M. 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
- Assistance Publique - Hôpitaux de Paris Tocilizumab improves significantly clinical outcomes of patients with moderate or severe COVID-19 pneumonia. April 27, 2020.
- Sherman RE, Anderson SA, Dal Pan GJ. Real-world evidence: what is it and what can it tell us? N Engl J Med. 2016;375:2293–2297.
- US Food and Drug Administration Use of electronic health record data in clinical investigations: guidance for industry. July, 2018.
- US Food and Drug Administration Framework for FDA's real-world evidence program. December, 2018.
- May S, Hosmer DW. A simplified method of calculating an overall goodness-of-fit test for the Cox proportional hazards model. Lifetime Data Anal. 1998;4:109–120.
- Ho D, Imai K, King G, Stuart E. Matching as nonparametric preprocessing for reducing model dependence in parametric causal inference. Polit Anal. 2007;15:199–236.
- Stuart EA. Matching methods for causal inference: a review and a look forward. Stat Sci. 2010;25:1–21.
- Martinez-Sanz J, Muriel A, Ron R. Effects of tocilizumab on mortality in hospitalized patients with COVID-19: a multicenter cohort study. medRxiv. 2020 doi: 10.1101/2020.06.08.20125245. published online June 9. (preprint)
- Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med. 2020;18:164.
- Teijaro JR. Cytokine storms in infectious diseases. Semin Immunopathol. 2017;39:501–503.
- McGonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev. 2020;19
- Tan L, Kang X, Ji X. Validation of predictors of disease severity and outcomes in COVID-19 patients: a descriptive and retrospective study. Med (N Y) 2020 doi: 10.1016/j.medj.2020.05.002. published online May 19.
- Weinhold B, Bader A, Poli V, Rüther U. Interleukin-6 is necessary, but not sufficient, for induction of the human C-reactive protein gene in vivo. Biochem J. 1997;325:617–621.
- Ridker PM. C-reactive protein: eighty years from discovery to emergence as a major risk marker for cardiovascular disease. Clin Chem. 2009;55:209–215.
- Kermali M, Khalsa RK, Pillai K, Ismail Z, Harky A. The role of biomarkers in diagnosis of COVID-19: a systematic review. Life Sci. 2020;254
- Zhang L, Yan X, Fan Q. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. 2020;18:1324–1329.
- Cavalli G, De Luca G, Campochiaro C. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020;2:e325–e331.
- The RECOVERY Collaborative Group Dexamethasone in hospitalized patients with Covid-19: preliminary report. N Engl J Med. 2020 doi: 10.1056/NEJMoa2021436. published online July 17.
- Hernandez AV, Roman YM, Pasupuleti V, Barboza JJ, White CM. Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review. Ann Intern Med. 2020 doi: 10.7326/M20-2496. published online May 27.
Source: PubMed