Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM—a prospective, randomized, single-centre, open-label study

Niklas Broman,Thijs Feuth,Tytti Vuorinen,Mika Valtonen,Ulla Hohenthal,Eliisa Löyttyniemi,Tiina Hirvioja,Päivi Jalava-Karvinen,Harri Marttila,Marika Nordberg,Jarmo Oksi

doi:10.1016/j.cmi.2022.02.027

Niklas Broman, Thijs Feuth + Show 9 more

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https://doi.org/10.1016/j.cmi.2022.02.027

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Abstract

ObjectivesSevere COVID-19 is associated with an imbalanced immune response. We hypothesized that patients with enhanced inflammation, as demonstrated by increased levels of certain inflammatory biomarkers, would benefit from interleukin-6 blockage. MethodsPatients hospitalized with COVID-19, hypoxemia, and at least two of four markedly elevated markers of inflammation (interleukin-6, C-reactive protein, ferritin, and/or D-dimer) were randomized for tocilizumab (TCZ) plus standard of care (SoC) or SoC alone. The primary endpoint was clinical status at day 28 assessed using a seven-category ordinal scale, and the secondary endpoints included intensive care unit admission, respiratory support, and duration of hospital admission. ResultsClinical status at day 28 was significantly better in patients who received TCZ in addition to SoC compared with those who received SoC alone (p = 0.037). By then, 93% of patients who received TCZ (n = 53 of 57) and 86% of control patients (n = 25 of 29) had been discharged from the hospital. In addition, 47% of TCZ patients (n = 27 of 57) and 24% of control patients (n = 7 of 29) had resumed normal daily activities. The median length of hospitalization was 9 days (interquartile range, 7–12) in the TCZ group and 12 days (interquartile range, 9–15) in the control group (p = 0.014). DiscussionIn patients hospitalized with COVID-19, hypoxemia, and elevated inflammation markers, administration of TCZ in addition to SoC was associated with significantly better clinical recovery by day 28 and a shorter hospitalization compared with SoC alone.

Highlights

We hypothesized that IL-6 blockage would be beneficial in a subset of patients with enhanced inflammation, as indicated by increased levels of the markers IL-6, CRP, ferritin, and D-dimer
We conducted a prospective, randomized, single-centre, openlabel study on the effect of TCZ and standard of care (SoC) versus SoC alone (2:1) in patients hospitalized with COVID-19, respiratory insufficiency, and systemic inflammation fulfilling certain laboratory criteria (COVIDSTORM studyeCOVID-19: Salvage Tocilizumab as a Rescue Measure, NCT04577534)
Patients receiving TCZ in addition to SoC displayed a significantly better clinical recovery by day 28 compared with patients receiving SoC alone

Summary

Introduction

N. Broman et al / Clinical Microbiology and Infection 28 (2022) 844e851 by thromboembolic or immunothrombotic events [5e7], and elevated levels of D-dimer are associated with increased mortality rates [8]. SARS-CoV-2 infection induces immune dysfunction, widespread endothelial injury, and complement-associated coagulopathy in severe cases [9]. Tocilizumab (TCZ), an IL-6 receptor antagonist, has been found effective in the treatment of severe SARS-CoV-2 infection by reducing the likelihood of progression to the composite outcome of mechanical ventilation or death and, when administered within 24 hours of intensive care unit (ICU) admission, by improving outcomes including survival [10,11]. In a meta-analysis, administration of an IL-6 blocker was associated with reduced mortality 28 days after randomization without increased risk of secondary infection [12]. We hypothesized that IL-6 blockage would be beneficial in a subset of patients with enhanced inflammation, as indicated by increased levels of the markers IL-6, CRP, ferritin, and D-dimer

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