key: cord-313627-g1iqhsdk
authors: Zou, Xiaojing; Fang, Minghao; Li, Shusheng; Wu, Liang; Gao, Bing; Gao, Hong; Ran, Xiao; YiBian,; Li, Renjie; Yu, Shanshan; Ling, Jianmin; Li, Donghui; Tian, Deying; Huang, Jiao
title: Characteristics of liver function in patients with SARS-CoV-2 and chronic HBV co-infection
date: 2020-06-15
journal: Clin Gastroenterol Hepatol
DOI: 10.1016/j.cgh.2020.06.017
sha: 
doc_id: 313627
cord_uid: g1iqhsdk

Summary Background and aims Coronavirus disease 2019 (COVID-19) is a major global health threat. We aimed to describe the characteristics of liver function in patients with SARS-CoV-2 and chronic hepatitis B virus (HBV) co-infection. Methods We enrolled all adult patients with SARS-CoV-2 and chronic HBV co-infection admitted to Tongji Hospital from February 1 to February 29, 2020. Data of demographic, clinical characteristics, laboratory tests, treatments, and clinical outcomes were collected. The characteristics of liver function and its relation with the severity and prognosis of disease were described. Results Of 105 SARS-CoV-2 and chronic HBV co-infected patients, elevated levels of liver test were seen in several patients at admission, including elevated levels of alanine aminotransferase (22,20.95%), aspartate aminotransferase (29, 27.62%), total bilirubin (7, 6.67%), gamma-glutamyl transferase (7, 6.67%) and alkaline phosphatase (1, 0.95%). The values of the indices mentioned above increased substantially during hospitalization (all P<0.05). 14 (13.33%) patients developed liver injury. Most of them (10, 71.43%) recovered after 8 (range 6-21) days. Notably, 4 (28.57%) patients rapidly progressed to acute-on-chronic liver failure. The proportion of severe COVID-19 was higher in patients with liver injury (P= 0.042). Complications including ACLF, acute cardiac injury and shock happened more frequently in patients with liver injury (all P<0.05). The mortality was higher in individuals with liver injury (28.57% vs 3.30%, P=0.004). Conclusion Liver injury in patients with SARS-CoV-2 and chronic HBV co-infection was associated with severity and poor prognosis of disease. During the treatment of COVID-19 in chronic HBV-infected patients, liver function should be taken seriously and evaluated frequently.

In December 2019, pneumonia caused by severe acute respiratory syndrome 2 coronavirus 2 (SARS-CoV-2), now known as coronavirus disease 2019 (COVID-19), 3 was first reported in Wuhan, China. It has subsequently spread throughout China and 4 other countries. A total of 750,890 cases and 36, 405 deaths had been reported all over 5 the word by March 31, 2020. 1 It has emerged as a major global health threat. 6 According to recent reports, 2-11% of COVID-19 patients had liver comorbidities and 7 14-35% cases have been reported with abnormal levels of alanine aminotransferase 8 (ALT) and aspartate aminotransferase (AST) during disease progression. 2-5 However, 9 the exact cause of preexisting liver conditions had not been outlined in these studies. In this study, we aimed to describe the characteristics of liver function and its 3 relation with severity and prognosis in patients with SARS-CoV-2 and chronic HBV 4 co-infection, in order to provide evidence for the clinical treatment of these specific 5 patients and contribute to improving their prognosis. This is a single-center, retrospective study of 105 patients with SARS-CoV-2 and 9 chronic HBV co-infection hospitalized at Tongji hospital. Tongji hospital is one of the 10 major comprehensive medical treatment centers and assigned for the treatments for 11 severe COVID-19 patients by the government. We recruited inpatients from February 12 1 to February 29, 2020, who had been diagnosed as COVID-19 and chronic HBV 13 infection according to WHO interim guidance and AASLD guidelines. 9, 10 All patients 14 had a history of chronic HBV infection and tested positive for HBsAg at admission.

Laboratory confirmation of COVID-19 was performed by the local health authority as 16 previously described. 7 The ethics committee of Tongji Hospital approved this study 17 (TJ-IRB20200225).

Data extraction was performed by a trained team of physicians using a standardized 20 form to collect data on demographic characteristics, duration from illness onset to 21 hospitalization, underlying chronic medical conditions, symptoms from onset to 22 admission, continuous laboratory tests, treatments, complications and outcomes from 1 electronic medical records. The information on anti-HBV treatment was collected by 2 medical history. HBV serological markers were tested using commercially available 3 microparticle enzyme immunoassay kits (Axsym, Abbott Laboratories, Abbott Park, 4 IL, USA). HBsAg > 0.05 IU/ml was HBsAg-positive. Hepatitis B virus e antigen 5 (HBeAg) <1 IU/ml and ≥1 IU/ml mean HBeAg-negative and HBeAg-positive 6 respectively.

Severe illness of COVID-19 was defined as one of the following: respiratory rate > 8 30 breaths/min; severe respiratory distress; or SpO2 ≤ 93% on room air. 9 Liver test 9 abnormalities were defined by the abnormal of the following indices in serum: 10 ALT>41 units/liter (U/L), AST>40 U/L, gamma-glutamyl transferase (γ-GT)>71 U/L, 11 alkaline phosphatase (ALP)>130 U/L, or total bilirubin (TBIL)>26 µmol/L. Liver 12 injury was defined as ALT and/or AST over 3 ULN, and/or TBIL over 2 ULN. 11

Acute-on-chronic liver failure (ACLF) was defined as TBIL ≥5 mg/dL (85 µmol/L) 14 and coagulopathy (international normalized ratio (INR) ≥1.5 or prothrombin activity 15 (PTA)< 40%) complicated within 4 weeks by clinical ascites and/or encephalopathy 16 in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis, 

Of 105 patients with SARS-CoV-2 and chronic HBV co-infection, 14(13.33%) had 11 liver injury and 4 (3.81%) developed ACLF during the hospitalization. Liver injury was more common in males than in females (92.86% vs. 46.15%, 5 P=0.001). The incidence of fever was higher in patients with liver injury (P=0.011). were still hospitalized; 55 (52.38%) patients had been discharged, and 7 (6.67%) 7 patients died. The mortality was significantly higher in individuals with liver injury 8 (28.57% vs. 3.30%, P=0.004) ( Table 3) . In the present study, we found that liver test abnormalities were relatively common 1 in patients with SARS-CoV-2 and chronic HBV co-infection, and the values of ALT, 2 AST, TBIL, ALP and γ-GT increased substantially during hospitalization. A small part 3 of patients developed liver injury. Patients with liver injury were more likely to 4 develop severe illness and had a worse prognosis including higher mortality and 5 incidence of complications. 6 The present study reported evidence of liver injury in patients with SARS-CoV-2 7 and chronic HBV co-infection. Several patients had various abnormal liver tests.

According to previous studies, the incidence of ALT and AST abnormalities were 9 14.34%-29.5% and 17.9%-35%, respectively, 2, 4, 5, 16 which were similar to ours. Liver 10 injury occurred in 21.5% of patients with COVID-19 during the hospitalization as Cai 11 Q et al. reported, 17 which was higher than that in our study (13.33%). Several reasons 12 may explain it. Firstly, the two studies used different criteria for liver injury. We 13 defined ALT and/or AST over 3 ULN, and/or TBIL over 2 ULN as liver injury 14 according to the protocol for prevention, diagnosis and treatment of liver injury in 15 COVID-19, 11 while liver injury was defined as ALT and/or AST over 3 ULN, ALP, 16 GGT, and/or TBIL over 2 ULN in the study of Cai Q et al. Secondly, the interval from 17 onset to admission of patients in the present study was 10 days, which may lead to the 18 missed diagnosis of early liver injury for lack of data prior to admission. Furthermore, 19 there is heterogeneity in the population characteristics included in the two studies.

Whether liver injury in COVID-19 is worth taking seriously remains 21 controversial. 18, 19 A recent study showed the presence of abnormal liver tests and liver injury were associated with the progression to severe pneumonia. 17 In our study, 1 patients with liver injury were more likely to develop severe illness and had a worse 2 prognosis including higher mortality and incidence of complications such as ACLF, 3 acute cardiac injury and shock. Liver injury happened to most patients within one 4 week, and recovered normality after several days. However, four chronic 5 HBV-infected patients deteriorated rapidly after SARS-CoV-2 co-infection with 6 progressively elevated jaundice, coagulation dysfunction and ascites, and were 7 diagnosed as ACLF. Eventually, they all died of multi-organ failure. Those with liver 8 injury but no coagulation dysfunction generally went on to recover. These findings 9 indicate that liver injury in patients with SARS-CoV-2 and chronic HBV co-infection 10 was associated with disease severity and worse prognosis. Liver function should be 11 evaluated more frequently in these special individuals, especially within a week after 12 admission. Once liver injury occurs, it should be treated timely in order to prevent 13 poor prognosis, particularly for those with coagulation dysfunction. 14 Drug-induced liver injury has been paid more attention in recent years. Intravenous 15 methylprednisolone was reported to be associated with acute liver injury, while data 16 on association between oral methylprednisolone and liver injury is insufficient. 20 In 17 the present study, more patients with liver injury received methylprednisolone. this study received these drugs. No difference was observed in the use of these drugs 22 between patients with and without liver injury, expect interferon atomization therapy, 1 which was more given to patients with liver injury. However, in the present study, not 2 all patients experienced liver injury after these treatments. 3 patients experienced liver 3 injury before methylprednisolone therapy and 2 patients experienced liver injury 4 before interferon atomization therapy. Therefore, the association between these drugs 5 and liver injury could not be further analyzed. 20 Lancet Gastroenterol Hepatol2020. Epub ahead of print. Death 7 (6.67) 4 (28.57) 3 (3.30) 0.004 Data are median (IQR) or n (%). NIV: non-invasive ventilation. IMV: invasive mechanical ventilation. ARDS: acute respiratory distress syndrome. ACLF: acute-on-chronic liver failure.

We described the characteristics of liver function and its relation with severity and prognosis in patients with SARS-CoV-2 and chronic hepatitis B virus (HBV) co-infection.

Patients with SARS-CoV-2 and chronic HBV co-infection who developed liver injury were more likely to progress into severe illness and had a worse prognosis including higher mortality and incidence of complications such as acute-on-chronic liver failure, acute cardiac injury and shock.

Liver function should be evaluated more frequently in patients with SARS-CoV-2 and chronic HBV co-infection, especially within one week after admission.

WHO. Coronavirus disease 2019 (COVID-19) Situation Report-71. Available at: 15

Clinical features of patients infected with 2019 18 novel coronavirus in Wuhan

Epidemiological and clinical characteristics of 20 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

 10 We want to thank all participants in the study. We would like to thank all the 11 medical staffs at Tongji Hospital who contributed to the study.