Circulating Proteins\nAssociated with Anti-IL6 Receptor\nTherapeutic Resistance in the Sera of Patients with Severe COVID-19

Circulating\nproteomes provide a snapshot of the physiological state\nof a human organism responding to pathogenic challenges and drug interventions.\nThe outcomes of patients with COVID-19 and acute respiratory distress\nsyndrome triggered by the SARS-CoV2 virus remain uncertain. Tocilizumab\nis an anti-interleukin-6 treatment that exerts encouraging clinical\nactivity by controlling the cytokine storm and improving respiratory\ndistress in patients with COVID-19. We investigate the biological\ndeterminants of therapeutic outcomes after tocilizumab treatment.\nOverall, 28 patients hospitalized due to severe COVID-19 who were\ntreated with tocilizumab intravenously were included in this study.\nSera were collected before and after tocilizumab, and the patient’s\noutcome was evaluated until day 30 post-tocilizumab infusion for favorable\ntherapeutic response to tocilizumab and mortality. Hyperreaction monitoring\nmeasurements by liquid chromatography–mass spectrometry-based\nproteomic analysis with data-independent acquisition quantified 510\nproteins and 7019 peptides in the serum of patients. Alterations in\nthe serum proteome reflect COVID-19 outcomes in patients treated with\ntocilizumab. Our results suggested that circulating proteins associated\nwith the most significant prognostic impact belonged to the complement\nsystem, platelet degranulation, acute-phase proteins, and the Fc-epsilon\nreceptor signaling pathway. Among these, upregulation of the complement\nsystem by activation of the classical pathway was associated with\npoor response to tocilizumab, and upregulation of Fc-epsilon receptor\nsignaling was associated with lower mortality.