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

Muhović, D; Bojovic, Jelena Borovinic; Bulatović, Ana; Vukčević, Batrić; Ratković, Marina; Lazović, Ranko; Smolović, Brigita

doi:10.1111/liv.14516

Cited by 105 publications

(105 citation statements)

References 15 publications

(29 reference statements)

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“…5,7 The most common side effects of tocilizumab include headache and hypertension but, rarely, hepatotoxicity ranging from mild transaminases elevation to severe drug-induced liver injury (DILI) can occur. 8 Currently, data on hepatotoxicity of tocilizumab in COVID-19 disease are limited and inconclusive.…”

Section: Introductionmentioning

confidence: 99%

Tocilizumab and liver injury in patients with COVID-19

Serviddio

Villani

Stallone

et al. 2020

Therap Adv Gastroenterol

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Current mortality rate in patients with COVID-19 disease is about 2%, whereas 5% of patients require admission to the intensive care unit. It is assumed that interleukin (IL)-6 may be involved in the pathogenesis of severe COVID-19 infections; therefore, in the absence of a specific antiviral therapy, some authors have suggested that tocilizumab – a drug used to block the signal transduction pathway of IL-6 – could have beneficial effects in the management of severe COVID-19 disease. However, mild-to-moderate elevation in transaminases and drug-induced liver injury have been observed in patients treated with tocilizumab. We present seven cases of patients with elevated liver enzymes [up to five times the upper limit of normal (ULN)] at baseline who received tocilizumab for life-threatening COVID-19 disease. All patients had no history of liver or pulmonary disease and were admitted for acute hypoxemic respiratory failure, dyspnea and fever due to COVID-19 bilateral pneumonia. IL-6 was available in six patients, and was significantly increased particularly in those with severe impairment of lung function. All patients received tocilizumab (8 mg/kg/day) for two consecutive days because of lack of improvement after hydroxychloroquine, azithromycin and lopinavir/ritonavir treatment. After tocilizumab administration, clinical condition rapidly improved and liver function test normalized within 3 weeks of treatment. Tocilizumab may be effective for the treatment of severe COVID-19 disease, even in patients with elevated liver function tests. Further studies are needed to evaluate the impact of tocilizumab use on liver function tests in patients with pre-existing chronic liver disease.

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Section: Introductionmentioning

confidence: 99%

Tocilizumab and liver injury in patients with COVID-19

Serviddio

Villani

Stallone

et al. 2020

Therap Adv Gastroenterol

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“…Initial studies in COVID-19 patients with tocilizumab (Klopfenstein et al, 2020;Luo P. et al, 2020;Toniati et al, 2020) and baricitinib (Cantini et al, 2020) have shown promising results. However, tocilizumab use requires caution in patients with hepatic impairment and can induce liver injury in some COVID-19 patients (Muhovic et al, 2020). The potential for additional opportunistic pulmonary infection is also associated with monoclonal antibodies such as tocilizumab.…”

Section: Sars-cov-2 and Raas Pathwaymentioning

confidence: 99%

COVID-19 Usurps Host Regulatory Networks

2020

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE2) on the cell surface and this complex is internalized. ACE2 serves as an endogenous inhibitor of inflammatory signals associated with four major regulator systems: the renin-angiotensin-aldosterone system (RAAS), the complement system, the coagulation cascade, and the kallikrein-kinin system (KKS). Understanding the pathophysiological effects of SARS-CoV-2 on these pathways is needed, particularly given the current lack of proven, effective treatments. The vasoconstrictive, prothrombotic and pro-inflammatory conditions induced by SARS-CoV-2 can be ascribed, at least in part, to the activation of these intersecting physiological networks. Moreover, patients with immune deficiencies, hypertension, diabetes, coronary heart disease, and kidney disease often have altered activation of these pathways, either due to underlying disease or to medications, and may be more susceptible to SARS-CoV-2 infection. Certain characteristic COVID-associated skin, sensory, and central nervous system manifestations may also be linked to viral activation of the RAAS, complement, coagulation, and KKS pathways. Pharmacological interventions that target molecules along these pathways may be useful in mitigating symptoms and preventing organ or tissue damage. While effective anti-viral therapies are critically needed, further study of these pathways may identify effective adjunctive treatments and patients most likely to benefit.

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“…Other drugs described as having the potential to cause hepatotoxicity in COVID-19 included hydroxychloroquine (n=1, 12.5%), tocilizumab (n=2, 25%), and remdesivir (n=1, 12.5%). 12,18,[54][55][56][57][58][59] The methodological characteristics of the finalised studies were also analysed. The largest number of the studies were retrospective observational studies (n=26, 41.9%), followed by meta-analyses (n=10, 16.1%), case reports (n=9, 14.5%), case series (n=7, 11.3%), prospective observational studies (n=3, 4.8%), and others Table 1).…”

Section: Characteristics Of Studiesmentioning

confidence: 99%

“…A number of drugs currently in use have hepatotoxic potential, which might be further exaggerated in the setting of chronic liver disease (CLD). 12,56,58 The mechanisms for individual drugs are not clearly defined.…”

Section: Drug-induced Hepatotoxicitymentioning

confidence: 99%

“…The drugs currently used to manage COVID-19 infection also carry hepatotoxic potential. Muhović et al 56 reported a 40-fold rise in transaminases following two doses of tocilizumab, an interleukin-6 receptor antagonist, which regressed 10 days later. Morena et al 59 also reported elevated liver enzymes in 29% of patients who were on tocilizumab.…”

Section: Drug-induced Hepatotoxicity In Covid-19mentioning

confidence: 99%

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Incidence, patterns, risk factors, and histopathological findings of liver injury in coronavirus disease 2019 (COVID-19): a scoping review

et al. 2020

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Background: Coronavirus disease 2019 (COVID-19) exhibits many extrapulmonary manifestations, including liver injury. This scoping review aimed to provide insight into the incidence, patterns, risk factors, histopathological findings, and relationship with disease severity of COVID-19-associated liver injury. Furthermore, we identified existing gaps in the research on the hepatic manifestations of COVID-19 and highlighted areas for future investigations. Methods: A scoping review was conducted following the methodological framework suggested by Arksey and O'Mallay. Five online databases, along with grey literature, were searched for articles published until 22 May 2020, and we included 62 articles in the review. The research domains, methodological characteristics, and key conclusions were included in the analysis. Results: Retrospective observational studies comprised more than one third (41.9%) of the included publications, and 77.8% were conducted on living patients. The incidence of liver injury varied widely across the studies (4.8%-78%), and liver injury was frequently associated with severe COVID-19. We identified the following risk factors for liver injury: male sex, lymphopoenia, gastrointestinal involvement, old age, increased neutrophil count,

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

Cited by 105 publications

References 15 publications

Tocilizumab and liver injury in patients with COVID-19

Tocilizumab and liver injury in patients with COVID-19

COVID-19 Usurps Host Regulatory Networks

Incidence, patterns, risk factors, and histopathological findings of liver injury in coronavirus disease 2019 (COVID-19): a scoping review

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