Tocilizumab to Prevent Ventilatory Support for Severe Worsening COVID-19 Pneumonia: A Propensity Score Analysis

Background: High levels of serum Interleukin-6 correlate with disease severity in COVID-19 pneumonia. We hypothesized that tocilizumab (a recombinant humanized anti-IL-6 receptor) could improve outcomes in selected patients with severe worsening COVID-19 pneumonia and high inflammatory parameters. Methods: The TOCICOVID study included a prospective cohort of patients aged 16-80 years with severe (requiring >6L/min of oxygen therapy to obtain Sp02 >94%) rapidly deteriorating (increase by ≥3L/min of oxygen flow within the previous 12 hours) COVID-19 pneumonia with ≥5 days of symptoms and high C-reactive protein levels who entered a compassionate use program of treatment with intravenous tocilizumab (8mg/kg with a maximum of 800mg per infusion; and if needed a second infusion 24 to 72 hours later) and a control group (retrospectively selected with the same inclusion criteria). Outcomes were assessed at D15 using inverse probability of treatment weighted (IPTW) methodology. Findings: Among the 96 patients included (81% male, mean (SD) age: 60 (12.5) years), underlying conditions, disease severity and concomitant medications were well balanced between groups (tocilizumab, n=49; control, n=47). In the IPTW analysis, t reatment with tocilizumab prevented the need for ventilatory support (49 vs. 87%, wHR: 0.42 [0.29–0.60]; p<0.001) and invasive mechanical ventilation (29% vs. 46%; wHR: 0.56 [0.34–0,90]; p=0.017) within D15 after baseline, with an acceptable safety profile . However, tocilizumab did not improve overall survival at D15 (wHR=0.69 [0.26 – 1.77], p=0.438). Among the patients still alive at D15 (n=87/96, 91%) , those treated with tocilizumab had a higher rate of oxygen withdrawal: 58% vs 41%, wHR=1.75 [1.13 – 2.74], p=0.012), with a shorter delay (10 vs 11 days; p=0.021). The levels of CRP, fibrinogen (p<0.001 for both variables) and neutrophil-to-lymphocyte ratios (p=0.03) were significantly lower in the tocilizumab group (interaction test, mixed model). Interpretation: These findings support the fostering of research efforts in the fight against COVID-19-induced inflammation. Funding Statement: All costs (including funding for tocilizumab) were beared by Foch hospital. Declaration of Interests: MR: investigator of NCT04315298 trial which investigates the efficacy and safety of Sarilumab (licensed by Sanofi) in hospitalized patients with COVID-19; non-financial support from Novartis Pharma SAS, Bristol Myers Squibb, Swedish Orphan Biovitrum (outside the submitted work); HS: non-financial support from Oxyvie; grants for Foch Fundation, Fonds de dotation pour la recherche en sante respiratoire, Philips Fundation (outside the submitted work); GG: non-financial support from Bard (outside the submitted work); YS: non-financial support from Astra Zeneca, Novartis Pharma, Bristol Myers Squibb, Sanofi Aventis France, Shire France, Chugai Pharma France, Pfizer SAS (outside the submitted work); JLC: personal fees and non-financial support from Novartis, Boehringer Ingelheim and Astra Zeneca; grants and other from LVL Air Liquide, outside the submitted work; JEK: none; MG: consulting fees from GlaxoSmithKline and Astra Zeneca (outside the submitted work); FA: investigator of NCT04315298 trial which investigates the efficacy and safety of Sarilumab (licensed by Sanofi) in hospitalized patients with COVID-19; all other authors declare no competing interest. Ethics Approval Statement: The TOCICOVID study was approved by the Foch IRB (approval number IRB00012437) and was registered on the National Institute of Health data platform INDS (n°4710280420).