key: cord-269083-8mjdb9yj
authors: Muhović, Damir; Bojović, Jelena; Bulatović, Ana; Vukčević, Batrić; Ratković, Marina; Lazović, Ranko; Smolović, Brigita
title: First case of drug‐induced liver injury associated with the use of tocilizumab in a patient with COVID‐19
date: 2020-06-01
journal: Liver Int
DOI: 10.1111/liv.14516
sha: 
doc_id: 269083
cord_uid: 8mjdb9yj

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.

interleukin 6 (IL-6). 1 Elevated levels of IL-6 are predictive of a fatal outcome in COVID-19. 1 Tocilizumab (TCZ) is a humanized recombinant monoclonal antibody that acts as an IL-6 receptor antagonist, specifically binding to soluble or membrane-type IL-6 receptors. 2 In the absence of specific antiviral therapy, the rationale for TCZ use in COVID-19 is based on the understanding that IL-6 plays an important role in COVID-19-induced cytokine storm-cytokine release syndrome (CRS)-characterized by an extreme auto-amplifying cytokine reaction which is followed by the infiltration of inflammatory monocytes/macrophages and lymphocytes into the lung. 2 IL-6-mediated decrease in human leukocyte antigen-DR isotype (HLA-DR) expression causes lymphoid function defects. 2 Severe DILI (drug-induced liver injury) is a very rare complication of TCZ therapy. 3 In this article, we describe the first case of a patient with severe COVID-19 pneumonia who developed DILI associated with the use of TCZ, marked by a 40-fold increase in transaminases levels.

On 10 March 2020, a previously healthy 52-year-old man returned from a 1-day business trip from Serbia to Montenegro. Two weeks later, he developed a fever (up to 39.2°C) and a dry cough. He tested positive for SARS-CoV-2 by reverse transcriptase polymerase chain reaction (RT-PCR) via nasal swab. The patient was admitted to a regional hospital and diagnosed with COVID-19 bilateral pneumonia.

He was treated according to the National Health Commission and State Administration of Traditional Chinese Medicine protocol for COVID-19. 4 Twelve days after admission, chest multi-slice computed tomography (MSCT) has shown ground-glass opacities and bilateral basal pulmonary consolidation. He required mechanical ventilation and was transferred to the intensive care unit (ICU).

For the first 4 days of treatment in ICU, the patient was sedated, mechanically ventilated, with stable vital parameters. His treatment included: chloroquine 500 mg twice daily (for the first 12 days before ICU); lopinavir/ritonavir 400/100 mg twice daily (for the first 12 days and 3 days in the ICU); methylprednisolone (60-80 mg daily throughout the ICU treatment); as well as ceftriaxone and azithromycin (throughout the entire treatment).

Six days after admission to the ICU, the patient's condition worsened and the control chest radiography showed the signs of disease progression. In laboratory analyses, C-reactive protein (CRP: 193 mg/L), IL-6 (143 pg/mL), fibrinogen (6.1 g/L), D-dimer (7600 ng/mL) were increased and lymphocyte count was decreased Subsequently, the patient's condition is complicated by bilateral pneumothorax and subcutaneous emphysema ( Figure 1 ). The pneumothorax was treated with drain thoracostomy.

Ten days after the administration of TCZ, transaminase levels, CPR, IL-6 and D-dimer were approaching the normal range ( Figure 2 ).

To date, despite the laboratory recovery and the cessation of CRS, his condition is still critical owing to the pulmonary issues.

Approximately 5% of patients with COVID-19 require admission to the ICU for severe pneumonia, acute respiratory distress syndrome, rapidly evolving respiratory insufficiency, multi-organ failure or CRS. 8 The pathological immune response depends on the cytokine group (IL-6, IL-2, IL-7, IL-10 and tumour necrosis factor α), but IL-6 is considered to be a major mediator in the pathogenesis of CRS. 1 phase reactants in most patients. 9 The study showed that a positive effect of TCZ is exhibited only after repeated doses in critically ill patients; also, there is no information on TCZ side effects in this study. 9 Morrison et al reported two cases of COVID-19 infection suffering hypertrigliceridaemia after induction of TCZ, one of which had elevated inflammatory biomarkers consistent with acute pancreatitis. 13 The authors hypothesize that TCZ interfered with the role of IL-6 in the free fatty acid uptake to the skeletal muscle. 13 severe infections, acute liver injuries, cytopenia, gastrointestinal ulcerations and perforations. 15 Hepatotoxicity with mild to moderate transaminases elevation is a well-known side effect of TCZ, but severe DILI is very rare complication of TCZ therapy. 3 On 10 December 2019, the Department of Health in Australian Government updated information on TCZ and hepatotoxicity; informing health professionals that eight serious liver injuries had been reported so far, and two of those eight cases required liver transplantation (according to one pharmaceutical company). 16 In most cases, TCZ resulted in severe F I G U R E 2 Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), C-reactive protein (CRP) and interleukine-6 (IL-6) in our patient with cytokine release syndrome caused by COVID-19, after the use of tocilizumab (TCZ). Twenty-four hours after tocilizumab administration, transaminase levels increased 40-fold, suggesting a drug-induced liver injury (DILI), but after 10 d, transaminase levels are almost normalized. At the same time CRP and IL-6 levels (laboratory parameters associated with cytokine release syndrome) are approaching to the normal range hepatic injury when used in combination with other potentially hepatotoxic drugs. 16 Most patients with severe COVID-19 have a history of simultaneous use of multiple drugs that can induce liver injury.

In our case, chloroquine treatment was discontinued 6 days before liver injury and antiviral treatment was discontinued 3 days before liver injury. The patient was also treated with a combination of antibiotics, azithromycin and ceftriaxone, in the ICU before hepatic injury occurred.

The incidence of mild liver injury in hospitalized patients with COVID-19 ranges from 14% to 53%, and increased liver enzymes are more commonly observed in men and in more severe cases. 17 Sun et al described several possible mechanisms of liver damage in 

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. 

Cytokine storm and immunomodulatory therapy in COVID-19: Role of chloroquine and anti-IL-6 monoclonal antibodies

Complex immune dysregulation in COVID-19 patients with severe respiratory failure

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury

National Institute of Diabetes and Digestive and Kidney Diseases

National Health Commission & State Administration of Traditional Chinese Medicine. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia

Lombardy Section Italian Society Infectious And Tropical Diseases. Vademecum for the treatment of people with COVID-19

Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; Clinical Practice Guideline Panel: Chair; Panel members; EASL Governing Board representative: EASL Clinical Practice Guidelines: drug-induced liver injury

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

Tocilizumab treatment in COVID-19: A single center experience

Can we use interleukin-6 (IL-6) blockade for coronavirus disease, (COVID-19)-induced cytokine release syndrome (CRS)?

Effective treatment of severe COVID-19 patients with tocilizumab

Off-label use of tocilizumab in patients with SARS-CoV-2 infection

Letter to the Editor: Acute hypertriglyceridemia in patients with COVID-19 receiving tocilizumab

Covid-19 pneumonia in a kidney transplant recipient successfully treated with tocilizumab and hydroxychloroquine

Tocilizumab (Actemra)

Therapeutic Goods Administration. Medicines Safety Update. Update -Tocilizumab and hepatotoxicity

COVID-19 and liver disease

COVID-19: abnormal liver function tests

First case of drug-induced liver injury associated with the use of tocilizumab in a patient with COVID-19