First case of drug‐induced liver injury 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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Most cited references 12

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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

Zunyou Wu, Jennifer M. McGoogan (2020)

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Effective treatment of severe COVID-19 patients with tocilizumab

Xiaoling Xu, Mingfeng Han, Tiantian Li … (2020)

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

Evangelos Giamarellos-Bourboulis, Mihai Netea, Nikoletta Rovina … (2020)

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

Contributors

Damir Muhović:

ORCID: https://orcid.org/0000-0002-0099-678X

damir_muhovic@yahoo.com

Journal

Journal ID (nlm-ta): Liver Int

Journal ID (iso-abbrev): Liver Int

Journal ID (doi): 10.1111/(ISSN)1478-3231

Journal ID (publisher-id): LIV

Title: Liver International

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1478-3223

ISSN (Electronic): 1478-3231

Publication date (Electronic): 01 June 2020

Electronic Location Identifier: 10.1111/liv.14516

Affiliations

[ ¹ ] Faculty of Medicine University of Montenegro Podgorica Montenegro

[ ² ] Department of Gastroenterohepatology Clinical Center of Montenegro Podgorica Montenegro

[ ³ ] Department of Pulmonology Clinical Center of Montenegro Podgorica Montenegro

[ ⁴ ] Department of Rheumatology Clinical Center of Montenegro Podgorica Montenegro

Author notes

[*] [* ] Correspondence

Damir Muhović, Department of Gastroenterohepatology, Clinical Center of Montenegro Ljubljanska bb, 20000 Podgorica, Montenegro.

Email: damir_muhovic@ 123456yahoo.com

Author information

Damir Muhović https://orcid.org/0000-0002-0099-678X

Article

Publisher ID: LIV14516

DOI: 10.1111/liv.14516

PMC ID: 7276916

PubMed ID: 32478465

SO-VID: d13751d8-2e4d-4f88-9aca-1417debcedd9

License:

This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

History

Date received : 05 May 2020

Date revision received : 11 May 2020

Date accepted : 12 May 2020

Page count

Figures: 2, Tables: 0, Pages: 5, Words: 6036

Custom metadata

source-schema-version-number 2.0

edited-state corrected-proof

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:08.06.2020

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: covid‐19,drug‐induced liver injury,hepatotoxicity,sars‐cov‐2,tocilizumab

Data availability:

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: covid‐19, drug‐induced liver injury, hepatotoxicity, sars‐cov‐2, tocilizumab