Corrigendum: Clinical characteristics and the role of IL-6 in acuteon-chronic liver failure patients with or without COVID-19: a multicenter paired cohort study

Ruoyu Yao ¹ Guofen Xu ¹ Xiujuan Fu ¹ Wenrui Zhang ¹ Han Wang ¹ Yu Chen ^2* Jia Yao ^1*

• ¹ Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, China
• ² Department of Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China

1IntroductionAcute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute liver injury and organ failure in patients with chronic liver disease (CLD) or cirrhosis, with a high risk of short-term mortality(Sarin et al., 2019). Amidst the coronavirus disease 2019 (COVID-19) pandemic, which has emerged as the most significant public health challenge in the 21st century, a growing body of research has documented cases of liver dysfunction in COVID-19 patients(Jothimani et al., 2020; Sun et al., 2020). Therefore, the persisting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection poses a substantial challenge for the management of ACLF patients.COVID-19 is characterized by respiratory symptoms such as fever, cough, and sputum production(Singh and Khan, 2020), in addition to varying degrees of liver injuries(Cichoz-Lach and Michalak, 2021). A large multicenter study on liver injury patterns of COVID-19 in Asia found that SARS-CoV-2 infection could lead to severe liver injury in patients with chronic liver disease, decompensating one fifth of cirrhosis and worsening the clinical status of these patients(Sarin et al., 2020). In addition, a North American multicenter paired study revealed a poor overall prognosis among patients with cirrhosis and COVID-19(Bajaj et al., 2021). Studies have shown that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) on human cells and triggers immune responses and inflammation, leading to injuries to multiple organs and tissues including the lungs, liver, and muscles(Ashraf et al., 2021; Gusev et al., 2022). SARS-CoV-2 has also been reported to induce dysregulated inflammatory responses and trigger cytokine storms(Fara et al., 2020). The progression of ACLF is closely associated with immune dysregulation, and the activation of systemic immune responses and inflammation is widely acknowledged as the central pathogenic mechanism of ACLF(Wu et al., 2010; Fyfe et al., 2018). Cytokines play a key role in the progression of ACLF, and the secretion of cytokines, including interleukin-6 (IL-6), triggers extensive hepatocyte death and exacerbates the decline in liver function(Casulleras et al., 2020). However, the impact of COVID-19 on the prognosis of ACLF patients remain unclear, and few studies have compared the outcomes of ACLF with or without COVID-19. As COVID-19 remains an established and ongoing health issue, ACLF patients will continue to be at risk of contracting COVID-19. Further clinical observation and research will help us understand the impact of COVID-19 on ACLF patients and optimize the management of this patient population.The present multicenter paired study aimed to compare the clinical symptoms, comorbidities, complications, laboratory data, and 28-day mortality rate between ACLF patients with and without COVID-19 and to elucidate the impact of COVID-19 on ACLF patients. 2Methods2.1Study design and subjectsAll patients hospitalized due to ACLF and all SARS-CoV-2-positive patients in Shanxi Bethune Hospital, Beijing You'an Hospital, and Jincheng General Hospital from December 2022 to August 2023 were retrospectively reviewed in this multicenter paired cohort study. The inclusion criteria were: (i) with a diagnosis of ACLF according to the Asian Pacific Association for the Study of the Liver (APASL) expert consensus on ACLF: acute hepatic insult manifesting as jaundice (TBIL≥85 µmol/L) and coagulopathy (INR ≥ 1.5 or PTA< 40%), complicated within 4 weeks by ascites and/or hepatic encephalopathy (HE) in a patient with previously diagnosed or undiagnosed chronic liver disease or cirrhosis (Sarin et al., 2019); (ii) with a diagnosis of COVID-19 according to the Diagnosis and Treatment Protocol for COVID-19 (Trial Version 10), which requests a positive COVID-19 nucleic acid test or COVID-19 antigen test; and (iii) aged 18 - 70 years. The exclusion criteria were: (i) with other lung infections (e.g., influenza A/B or pulmonary bacterial infection); (ii) with liver cancer and/or other malignant tumors; and (iii) with other disorders of the immune system.All the included ACLF patients were divided into ACLF+COVID-19 group and ACLF group according to the presence or absence of COVID-19. Patients in these two groups were matched 1:1 according to age, gender, etiology, and Model for End-stage Liver Disease-Sodium (MELD-Na) score at the time of admission. The ACLF+COVID-19 group and the COVID-19 group were matched 1:1 in terms of age at admission, gender, and illness severity (Figure 1). The study was conducted in accordance with the Declaration of Helsinki, and the research protocol was approved by Shanxi Bethune Hospital (NO: YXLL-2023-233). 2.2Collection of clinical dataThe basic demographic data and clinical information of each patient during hospitalization, including gender, age, etiology, symptoms, comorbidities, complications, and 28-day mortality rate, were collected from the electronic medical records. The laboratory data including blood cell counts, liver and kidney functions, coagulation-related indicators, and cytokines were also collected. The MELD-Na score, APASL ACLF Research Consortium (AARC) score, and Sequential Organ Failure Assessment (SOFA) score at admission and the MELD-Na score after 1 week were calculated. All the collected data were reviewed by the research team and double-checked by experienced physicians.All ACLF patients received hepatoprotective, enzyme-lowering, and anti-jaundice drug therapy, along with albumin supplementation. General supportive care and nonbiological artificial liver (NBAL) were applied. Molnupiravir was administered in the ACLF+COVID-19 group. Patients in the COVID-19 alone group were given antiviral therapy and general supportive care. 2.3Sample size calculationWith an attempt to investigate the clinical characteristics of ACLF patients with COVID-19, we divided the enrolled ACLF patients into ACLF+COVID-19 group and ACLF group. Preliminary experiments showed IL-6 levels of 155.33 ± 98.1 in the ACLF+COVID-19 group and 51.97 ± 56.48 in the ACLF group. Accordingly, a sample size of 12 patients per group was calculated using the PASS 2021 software (NCSS, LLC, USA) with a significance level (α) of 0.05, a power of 0.8, and an equal allocation ratio of 1:1.2.4Statistical analysisStatistical analysis was carried out using the SPSS software package (version 26.0; IBM). The normally distributed measurement data are presented as mean ± standard deviation and compared using independent samples t test. The non-normally distributed measurement data are presented as medians (interquartile ranges) and compared using a nonparametric test (Kruskal-Wallis test). Count data are described as frequency or percentage and compared using a Chi-square test or Fisher's exact test.