Effects of Steroids and Tocilizumab on the Immune Response Profile of Patients with COVID-19-Associated ARDS Requiring or Not Veno-Venous Extracorporeal Membrane Oxygenation

Vito Fanelli; Giorgia Montrucchio; Gabriele Sales; Umberto Simonetti; Chiara Bonetto; Francesca Rumbolo; Giulio Mengozzi; Rosario Urbino; Costanza Pizzi; Lorenzo Richiardi; Paola Cappello; Luca Brazzi

doi:10.3390/membranes11080603

Effects of Steroids and Tocilizumab on the Immune Response Profile of Patients with COVID-19-Associated ARDS Requiring or Not Veno-Venous Extracorporeal Membrane Oxygenation

Membranes (Basel). 2021 Aug 9;11(8):603. doi: 10.3390/membranes11080603.

Authors

Vito Fanelli^{1

2}, Giorgia Montrucchio^{1

2}, Gabriele Sales², Umberto Simonetti², Chiara Bonetto², Francesca Rumbolo³, Giulio Mengozzi³, Rosario Urbino², Costanza Pizzi⁴, Lorenzo Richiardi⁴, Paola Cappello^{5

6}, Luca Brazzi^{1

2}

Affiliations

¹ Department of Surgical Sciences, University of Turin, 10124 Torino, Italy.
² Department of Anaesthesia, Critical Care and Emergency, Città della Salute e della Scienza Hospital, University of Turin, 10124 Torino, Italy.
³ Clinical Biochemistry Laboratory, Città della Salute e della Scienza Hospital, University of Turin, 10124 Torino, Italy.
⁴ Department of Medical Sciences, University of Turin, 10124 Torino, Italy.
⁵ Department of Molecular Biotechnology and Health Sciences, University of Turin, 10124 Torino, Italy.
⁶ Center for Experimental and Medical Research Studies (CeRMS), Città della Salute e della Scienza Hospital, University of Turin, 10124 Torino, Italy.

Abstract

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving rescue therapy in patients with Acute Respiratory Distress Syndrome (ARDS). ECMO has been associated with development of lymphocytopenia that is also common in COVID-19. Hyperinflammation may complicate SARS-CoV-2 pneumonia, prompting therapy with steroids and immunomodulatory drugs. We aimed to evaluate the association of therapies such as steroids and Tocilizumab with trajectories of the total leukocytes, lymphocyte subpopulation count, and inflammatory and fibrinolysis markers in COVID-19-related ARDS, requiring or not VV-ECMO support. The association of the trajectories of the leukocytes, lymphocyte subpopulation count, and inflammatory and fibrinolysis markers with treatment with steroids (Steroids), Tocilizumab (Tocilizumab), both drugs (Steroids + Tocilizumab), and absence of treatment (No Treatment) were analyzed using mixed effects regression models, where ECMO was considered as a potential effect modifier. One hundred and thirty-nine leukocyte and eighty-one lymphocyte subpopulation counts were obtained from thirty-one patients who required (VV-ECMO, N = 13) or not (no VV-ECMO, N = 18) extracorporeal support. In both groups, treatment with Steroids + Tocilizumab was independently associated with a significant reduction of 46% and 67% in total lymphocytes, 22% and 60% in CD3⁺, and 61% and 91% in CD19⁺ (B lymphocytes) compared to those obtained without treatment, respectively. In the no VV-ECMO group, Tocilizumab was associated with a 79% increase in total lymphocytes and with a reduction in procalcitonin compared to no treatment. CD45⁺, CD3⁺CD4⁺ (Th cell), CD3⁺CD8⁺, CD4⁺/CD8⁺, the NK cell subpopulation, neutrophils, monocytes, and basophils were significantly reduced by Steroids + Tocilizumab without an effect modification by VV-ECMO support. In critically ill COVID-19 patients with ARDS, concomitant therapies with steroids and Tocilizumab, beside mitigating the inflammation and fibrinolysis, could reduce the total leukocyte, lymphocyte, and subpopulation count. Moreover, the effect of Tocilizumab in increasing the total lymphocytes and reducing procalcitonin might be blunted by VV-ECMO.

Keywords: COVID-19; Tocilizumab; acute respiratory distress syndrome; extracorporeal membrane oxygenation; lymphocytes; steroids.