Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy

Abstract

Background: Tocilizumab, a humanized monoclonal antibody, targets IL-6 receptors blocking downstream pro-inflammatory effects of IL-6. In preliminary reports it was suggested to be beneficial in patients with severe COVID-19.

Methods: In this open-label prospective study we describe clinical characteristics and outcome of 51 patients hospitalized with confirmed and severe COVID-19 pneumonia treated with tocilizumab intravenously. All patients had elevated IL-6 plasma level (>40 pg/mL) and oxygen saturation <93% in ambient air. Clinical outcomes, oxygen support, laboratory data and adverse events were collected over a follow-up of 30 days.

Results: Forty-five patients (88%) were on high-flow oxygen supplementation, six of whom with invasive ventilation. From baseline to day 7 after tocilizumab we observed a dramatic drop of body temperature and CRP value with a significant increase in lymphocyte count (p<0.001). Over a median follow-up time of 34 days from tocilizumab, 34 patients (67%) showed an improvement in their clinical severity class; 31 were discharged; 17 (33%) showed a worsening of their clinical status, of these 14 died (27%). The mortality rate was significantly associated with mechanical ventilation at baseline (83.3% vs 20% of patients on non-invasive oxygen support; p=0.0001). The most frequent side effects were an increase of hepatic enzymes (29%), thrombocytopenia (14%), and serious bacterial and fungal infections (27%).

Conclusion: Tocilizumab exerts a rapidly beneficial effect on fever and inflammatory markers, although no significant impact on the clinical outcome can be inferred by our results. Critically ill patients seem to have a high risk of serious infections with this drug.

Keywords: COVID-19; IL-6 inhibitors; tocilizumab.

Graphical abstract

Fig. 1

Concomitant anti COVID-19 therapies administered during hospitalization for each patient. The point zero vertical bar represents the time of tocilizumab administration. The horizontal lines indicate the timing and duration of hydroxychloroquine (A), lopinavir-ritonavir (B) and remdesivir (C) administration for each patient.

Fig. 2

A. Kaplan-Meier curves showing survival of participants with severe COVID-19 pneumonia treated with tocilizumab; B. Survival curves in the cohort stratified according to ventilation status at baseline.

Fig. 3

Change in oxygen support, and deaths over the 30-days follow-up. T0 was the day on which tocilizumab was initiated. CPAP, Continuous positive airway pressure.

Fig. 4

Cumulative Incidence of clinical improvement from baseline to day 30.The cumulative incidence of improving over time from the tocilizumab administration is shown by a competing risk survival analysis and death is handled as competing event. Dashed lines define the 95% confidence interval range.

Fig. 5

Changes in the values of lymphotytes (A), platelets (B), CRP (C) and ALT (D) after treatment with tocilizumab. The time points considered are: T0, the day of tocilizumab administration, day 1, day 3 and day 7 after treatment.