Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.

BACKGROUND: Many COVID-19 patients develop a hyperinflammatory response which activates blood coagulation and may contribute to the occurrence of thromboembolic complications. Blockade of interleukin-6, a key cytokine in COVID-19 pathogenesis, may improve the hypercoagulable state induced by inflammation. The aim of this study was to evaluate the effects of subcutaneous tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 receptor on coagulation parameters. METHODS: Hospitalized adult patients with laboratory-confirmed moderate to critical COVID-19 pneumonia and hyperinflammation, who received a single 324 mg subcutaneous dose of tocilizumab on top of standard of care were enrolled in this analysis. Coagulation parameters were measured before tocilizumab and at day 1, 3, and 7 after treatment. All patients were followed-up for 35 days after admission or until death. RESULTS: 70 patients (mean age 60 years, interquartile range 52-75) were included. Treatment with tocilizumab was associated with a reduction in D-dimer levels (-56%; 95% confidence interval [CI], -68% to -44%), fibrinogen (-48%; 95%CI, -60% to -35%), C-reactive protein (-93%; 95%CI, -99% to -87%), prothrombin time (-4%; 95%CI,-9% to 0.8%), and activated thromboplastin time (-4%; 95%CI,-8.7% to 0.8%), and an increase in platelet count (34%; 95%CI, 23% to 45%). These changes occurred already one day after treatment with sustained reductions throughout day 7. The improvement in coagulation was consistently observed in patients receiving prophylactic or therapeutic dose anticoagulants, and was paralleled by a rapid improvement in respiratory function. CONCLUSIONS: Subcutaneous tocilizumab was associated with significant improvement of blood coagulation parameters independently of thromboprophylaxis dose.

Low-dose subcutaneous tocilizumab to prevent disease progression in patients with moderate COVID-19 pneumonia and hyperinflammation.

AIM: This study aimed to evaluate the safety and efficacy profile of low-dose tocilizumab (TCZ), to prevent disease progression, subcutaneously administered to patients with moderate COVID-19 pneumonia and hyperinflammation. METHODS: Clinical characteristics and outcomes were retrospectively analysed of patients - with laboratory-confirmed bilateral COVID-19 pneumonia, hyperinflammation (C-reactive protein (CRP) ≥20 mg/dL), no hypoxaemia (oxygen saturation >90%), and no contraindications to TCZ - who were treated with subcutaneous TCZ (324 mg) administered within 48 h from hospitalization on top of standard of care (SOC). They were compared with matched controls treated with SOC only before TCZ was available at the institution. Clinical data were available for all patients until death or until day 35 for those discharged from hospital. FINDINGS: Ten consecutive patients (six males, median age 55 years) treated with TCZ on top of SOC, and ten patients (six males, median age 56 years) treated with SOC only were included. TCZ was well-tolerated with no clinically relevant adverse events. TCZ was associated with a reduction in CRP at day 1 (-50%, IQR -28 to -80) and day 3 (-89%, IQR -79 to -96; p = 0.005 for within-group), whereas there was no significant change in CRP values in the SOC group (p < 0.001 for between-group comparisons at both time points). TCZ resulted in a parallel improvement in oxygenation, as assessed by the ratio of partial pressure of oxygen to fraction of inspired oxygen (P/F) ratio, which increased at day 1 (+11%, IQR +6 to +16; p = 0.005 for within-group and p = 0.006 for between-group comparisons), and day 3 (+23%, IQR +16 to +34; p = 0.005 for within-group and p = 0.003 for between-group comparisons). None of the TCZ-treated patients had disease progression, defined as requirement of oxygen therapy or mechanical ventilation, whereas progression occurred in five (50%) patients among the SOC group. CONCLUSIONS: Low-dose subcutaneous TCZ may be a safe and promising therapeutic option administered on top of SOC to prevent disease progression in hospitalised patients with moderate COVID-19 and hyperinflammation.