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      First case of drug‐induced liver injury (DILI) associated with the use of tocilizumab in a patient with COVID‐19

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          Abstract Background and Aims Tocilizumab (TCZ; interleukine‐6 receptor antagonist) has been proposed to treat severe forms of Coronavirus disease‐19 (COVID‐19) because interleukine‐6 plays an important role in COVID‐19‐induced cytokine storm. Several clinical studies have shown very good effects of TCZ in patients with COVID‐19, with a few minor side effects reported. Only eight serious liver injuries caused by TCZ were reported before being used in the treatment of patients with COVID‐19. Considering the significantly increased use of TCZ for the treatment of COVID‐19, we would like to warn of its rare but possible serious hepatotoxicity, especially when used together with other hepatotoxic drugs. Methods We describe a patient with COVID‐19‐induced cytokine storm who developed drug‐induced liver injury associated with the use of TCZ. Results One day after TCZ administration, serum transaminase levels increased 40‐fold. Nevertheless, TCZ had a positive effect on clinical and laboratory parameters in cytokine storm, with transaminases values normalizing in 10 days. Conclusions This is the first reported case of DILI caused by TCZ in a COVID‐19 patient. Intensive liver function monitoring is imperative in COVID‐19 patients, because of frequent polypharmacy with potentially hepatotoxic drugs.

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          Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

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            Effective treatment of severe COVID-19 patients with tocilizumab

            Significance In patients with coronavirus disease 2019, a large number of T lymphocytes and mononuclear macrophages are activated, producing cytokines such as interleukin-6 (IL-6), which bind to the IL-6 receptor on the target cells, causing the cytokine storm and severe inflammatory responses in lungs and other tissues and organs. Tocilizumab, as a recombinant humanized anti-human IL-6 receptor monoclonal antibody, can bind to the IL-6 receptor with high affinity, thus preventing IL-6 itself from binding to its receptor, rendering it incapable of immune damage to target cells, and alleviating the inflammatory responses.
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              Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

              Summary Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7–8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.
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                Author and article information

                Journal
                Liver International
                Liver Int
                Wiley
                1478-3223
                1478-3231
                May 17 2020
                Affiliations
                [1 ]Faculty of Medicine University of Montenegro 20000 Podgorica Montenegro
                [2 ]Department of Gastroenterohepatology Clinical Center of Montenegro 20000 Podgorica Montenegro
                [3 ]Department of Pulmonology Clinical Center of Montenegro 20000 Podgorica Montenegro
                [4 ]Department of Rheumatology Clinical Center of Montenegro 20000 Podgorica Montenegro
                Article
                10.1111/liv.14516
                d13751d8-2e4d-4f88-9aca-1417debcedd9
                © 2020

                http://onlinelibrary.wiley.com/termsAndConditions#vor

                http://doi.wiley.com/10.1002/tdm_license_1.1

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