Efficacy of tocilizumab in patients with COVID-19 ARDS undergoing noninvasive ventilation

Francesco Menzella,Gloria Montanari,Carlo Salvarani,Francesco Livrieri,Marco Massari,Chiara Barbieri,Roberto Piro,Luca Ghidorsi,Nicola Facciolongo,Patrizia Ruggiero,Giulia Ghidoni,Chiara Scelfo,Claudia Castagnetti,Pamela Mancuso,Francesco Falco,Chiara Catellani,Eleonora Casalini,Giorgia Gibellini,Matteo Fontana

doi:10.1186/s13054-020-03306-6

Abstract

BackgroundThe severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely variable, ranging from asymptomatic patients to those who develop severe acute respiratory distress syndrome (ARDS). As for now, there are still no really effective therapies for coronavirus disease 2019 (COVID-19). Some evidences suggest that tocilizumab (TCZ) may avoid the progression of severe COVID-19. The aim of this retrospective case-control study was to analyze the efficacy and safety of TCZ in patients with COVID-19 ARDS undergoing noninvasive mechanical ventilation (NIV).MethodsSeventy-nine consecutive patients with severe COVID-19 pneumonia and worsening acute respiratory failure (ARF) were admitted to the Pulmonology Unit of Azienda USL of Reggio Emilia-IRCCS. All patients were inflamed (elevated CRP and IL-6 levels) and received NIV at admission according to the presence of a pO2/FiO2 ratio ≤ 200 mmHg. The possibility of being treated with TCZ depended on the drug availability. The primary outcome was the in-hospital mortality rate. A secondary composite outcome of worsening was represented by the patients who died in the pulmonology unit or were intubated.ResultsOut of 79 patients, 41 were treated with TCZ. Twenty-eight patients received intravenous (IV) TCZ and 13 patients received subcutaneous (SC) TCZ. In-hospital overall mortality rate was 38% (30/79 patients). The probabilities of dying and being intubated during the follow-up using Kaplan-Meier method were significantly lower in total patients treated with TCZ compared to those of patients not treated with TCZ (log-rank p value = 0.006 and 0.036, respectively). However, using Cox multivariate analyses adjusted for age and Charlson comorbidity index only the association with the reduced risk of being intubated or dying maintained the significance (HR 0.44, 95%CI 0.22–0.89, p = 0.022). Two patients treated with TCZ developed cavitating lung lesions during the follow-up.ConclusionsThis study shows that TCZ treatment may be effective in COVID-19 patients with severe respiratory impairment receiving NIV. More data on safety are required. Randomized controlled trials are needed to confirm these results.

Highlights

The severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely variable, ranging from asymptomatic patients to those who develop severe acute respiratory distress syndrome (ARDS)
In the TCZ treatment group, C-reactive protein (CRP) levels were significantly lower at 72 h and 7 days after starting therapy compared with the standard therapy group (p = 0.02 and p = 0.001, respectively), while an increase in interleukin 6 (IL-6) levels was found at the same times, due to the known effect of TCZ that blocking IL-6 receptors increases the serum levels of free IL-6
Patients treated with TCZ were younger, had a lower Charlson comorbidity index, and received more frequently hydroxychloroquine compared to the standard therapy group (p = 0.005, p = 0.002, and p = 0.05, respectively); the other evaluated parameters were not different, including the number of comorbidities and SOFA index

Summary

Introduction

The severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely variable, ranging from asymptomatic patients to those who develop severe acute respiratory distress syndrome (ARDS). The severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely variable, ranging from asymptomatic patients to those who develop pneumonia with acute respiratory distress syndrome (ARDS) [1]. In SARS-CoV infections, elevated levels of serum proinflammatory cytokines (IFN-γ, IL-1, IL-6, IL-12, and TGFβ) and chemokines (CCL2, CXCL10, CXCL9, and IL-8) have been detected in patients with severe forms compared to less complicated cases [4]. Even in Middle East respiratory syndrome (MERS) infection, the presence of elevated levels of serum pro-inflammatory cytokines (IL-6 and IFN-α) and chemokines (IL-8, CXCL-10 and CCL5) is documented in the most severe forms compared to the milder ones [5]. It is important to note that the levels of IL6 in the blood of the patients with severe disease were higher than those observed in patients with milder disease and an association between elevated IL-6 serum levels and increased mortality rates was found [6, 7]

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Conclusion