key: cord-0687837-p0mzuor5
authors: Bekçibaşı, Muhammed; Arslan, Eyüp
title: Severe acute respiratory syndrome coronavirus 2 (SARS‐COV‐2) /Hepatitis B virus (HBV) Co‐infected Patients: A case series and review of the literature
date: 2021-06-06
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14412
sha: 3cec8021f12b0a5594f7f426d55b95728641104d
doc_id: 687837
cord_uid: p0mzuor5

OBJECTIVE: We aimed to determine whether severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)/hepatitis B virus (HBV) coinfection affects liver function and the outcome of the disease. METHODS: One hundred fifty‐six laboratories confirmed SARS‐CoV‐2 positive patients were followed up between 1 July and 31 December 2020 and analysed retrospectively. Continuous variables were compared with the independent samples t‐test. Categorical variables were compared using the Pearson's chi‐square or Fisher's exact test. A P value of less than .05 was considered statistically significant. RESULTS: The age range of the cohort was from 40 to 78 and 73 (46.8%) of 156 patients were male. There was no significant difference in age and gender distribution between 20 patients (12.8%) with SARS‐CoV‐2/HBV coinfection and 136 patients without HBV infection (87.2%) (P > .05). Liver function tests were higher in the SARS‐CoV‐2/HBV coinfected patient group but were not statistically significant. The levels of creatine kinase (CK) were significantly higher in coronavirus disease 2019 (COVID‐19) patients without HBV infection compared with the SARS‐CoV‐2/HBV coinfected patient group (P = .0047). Severe/critical illness was less common in the SARS‐CoV‐2/HBV coinfected patient group, and no deaths were observed. CONCLUSIONS: SARS‐CoV‐2/HBV coinfection did not change the severity and outcome of COVID‐19. However, the patients with SARS‐CoV‐2/HBV coinfection should be closely monitored for liver complications.

HBsAg seropositivity rate (7.3%) in the country. 9 We aimed to evaluate whether SARS-CoV-2/HBV coinfection affects liver function and the outcome of the disease.

This is a retrospective and single-centre study. The data of 410 patients who were followed up between 1 July and 31 December 2020 at the Bismil State Hospital with the diagnosis of COVID-19

were analysed retrospectively. One hundred seventy patients were excluded due to without serum HBV test results during hospitalisation, and 84 patients were excluded due to the negativity of SARS-CoV-2 PCR tests. One hundred fifty-six laboratories confirmed SARS-CoV-2 positive patients were included in the study. Clinical diagnosis, treatment and discharge criteria were determined according to the Ministry of Health of the Republic of Turkey COVID-19 reference guide. 10 Chronic HBV infection was defined as a laboratory confirmed group of the patients known to be HBsAg positive for more than 6 months. Eleven patients were carriers of inactive hepatitis B, and three patients were receiving oral antiviral therapy. Because the HBV-DNA status was not known, the disease stage of six patients could not be determined.

The patients with coinfection with hepatitis delta virus, hepatitis C virus, human immunodeficiency virus (HIV) and/or chronic liver diseases such as primary biliary cirrhosis, liver cirrhosis, autoimmune hepatitis and alcoholic hepatitis were excluded from the study. The stories, clinical findings, laboratory tests, radiological outcomes, microbiological tests and clinical course of the patients were analysed retrospectively.

Severe/critical illness was defined by the presence of any one of the following: 

The age range of the cohort was from 40 to 78, and 73 (46.8%) of 156 patients were male. There was no significant difference in age and gender distribution between 20 patients (12.8%) with SARS-CoV-2/HBV coinfection and 136 patients without HBV infection (87.2%) (P > .05).

There was no statistically significant difference in the level of 

• SARS-CoV-2/HBV coinfection does not change the severity and the outcome of COVID-19.

• Clinicians should closely monitor liver function of the patients with SARS-CoV-2/HBV coinfection. the HBV coinfection patient group. However, in the patient group without HBV infection, severe/critical illness was observed in 33 (24.3%) cases and death in 13 (9.6%) patients (Table 1) .

Because chronic HBV infection can progress with reactivations, the guidelines recommend that the patients with SARS-CoV-2/ HBV coinfected should continue their treatment without disruption and carefully monitored for reactivation. 11 The majority of studies show that SARS-CoV-2/HBV coinfection does not exacerbate liver damage. However, whether it affects the severity and outcome of COVID-19 disease has been controversial. 12 In our study, liver function tests of SARS-CoV-2/HBV coinfected patients were observed to be slightly higher compared with the control group at the time of admission and during hospitalisation. Nevertheless, coinfection did not have a negative effect on the course of COVID-19 disease.

However, elevated liver enzymes or laboratory abnormalities indicating hepatic exacerbation were not detected in the follow-up of SARS-CoV-2/HBV coinfected patients.

Serum CK levels are the most sensitive indicator of muscle damage. 13 It is common for COVID-19 patients to show signs of dehydration. In the case of severe disease, hypovolaemia may contribute to renal failure and thus a slight increase in CK levels. 14 In our study, serum CK levels in COVID-19 patients without HBV infection were significantly higher compared with the SARS-CoV-2/HBV coinfected patient group. In a recently published COVID-19 case series, it was concluded that high CK levels may be an early warning indicator for severe disease, consistent with our study. 15 concentrations were found significantly higher in nonsurvivors compared with recovered patients in the cohort studies of COVID-19. 16 The absence of death in the SARS-CoV-2/HBV coinfected patient group in our study and the lower rate of serious/critical patients may explain this difference in CK levels.

Although liver damage is common in COVID-19, severe liver damage is rarely observed. Liver function gradually returns to normal as clinical findings improve in the majority of patients. 12 In a study comparing COVID-19 patients with and without liver cirrhosis, no significant difference was observed in terms of liver biochemical abnormality. 17 Liver function tests are closely related to the severity and prognosis of COVID-19. 18 Although severe liver dysfunction has been described in patients with severe COVID-19, the influence of other factors such as sepsis-associated cholestasis, ischaemic hepatitis from hypoxaemia and hypotension and drug-induced liver injury should not be ruled out. 19 In a recent retrospective cohort study, ALT/AST elevation was commonly observed in COVID-19 patients and independently associated with adverse clinical outcomes. Use of ribavirin, interferon beta and/or lopinavir-ritonavir alone or in combination with corticosteroids has been independently associated with ALT/AST elevation. 20 However, it is recommended that off-label COVID-19 treatments be used with caution and close monitoring in patients with abnormal liver function. COVID-19 patients who are planned to use systemic high-dose corticosteroids or tocilizumab should be screened for HBV. Antiviral prophylaxis with nucleoside analogues is recommended in all of these patient groups with HBsAg positivity. 19 In some retrospective studies evaluating patients with SARS-CoV-2/HBV coinfection, it was shown that liver damage in SARS-CoV-2/HBV coinfected patients progressed with varying degrees of high function tests (AST, ALT, TBIL, ALP, GGT, etc), which is in accordance with our study. However, this difference was not found to be statistically significant when compared with the group of COVID-19

patients who were not infected with HBV. 21, 22 In a study involving a larger patient group, however, the levels of AST, ALT and APTT were significantly higher in the SARS-CoV-2/HBV coinfected group compared with the control group. 23 In another study in which 105 SARS-CoV-2/HBV coinfected patients were examined without forming a control group, liver damage was developed in 14 (13.3%) patients; four (28.6%) of these patients developed acute-on-chronic liver failure that resulted in death. 24 In the study conducted by Liu et al, 25 HBV reactivation was observed in three (15%) of 20 SARS-CoV-2/ HBV coinfected patients. The characteristics of liver injury in patients with SARS-CoV-2/HBV coinfection are summarised in Table 2 .

It has been shown in meta-analysis studies that the prevalence of chronic liver disease in COVID-19 patients is as low as 3.0%. 26 However, COVID-19 disease progression is significantly higher in patients with chronic liver disease compared with those without chronic liver disease, and acute-on-chronic liver failure may also occur in patients with compensated chronic liver disease. 27 In most retrospective analyses comparing SARS-CoV-2/HBV coinfected patients with the patients who has SARS-CoV-2 infection alone, no significant difference was shown between these two groups in terms of hospital stay, critical illness and prognosis. 7,21,22,28 Also in our study, SARS-CoV-2/HBV coinfection was not associated with the severity of COVID-19 or poor prognosis. However, some studies also reported contradictive results. In the study conducted by Wu et al, 23 the rate of severe/critical patients in 70 SARS-CoV-2/ HBV coinfected patients was found to be significantly higher than the group without HBV (32.9% vs. 15.3%). However, all patients with SARS-CoV-2/HBV coinfected were discharged, and there was no significant difference between the two groups in terms of hospital stay and mortality. In another study conducted with 15 SARS-CoV-2/HBV coinfected patients, it was reported that almost half of the HBV patients had a severe COVID-19 disease and had higher mortality rates. 29 The comparison of COVID-19 disease severity and clinical outcomes in SARS-CoV-2/HBV coinfected patients are summarised in Table 2 .

There are some limitations in our study. First, our study was limited to a single-centre, retrospective study, and we had a small number of patients. In addition, there may be selection bias in our study because we could only reach HBV serology results in half of the patients hospitalised due to COVID-19. Second, serum HBV-DNA levels of SARS-CoV-2/HBV coinfected patients could not be followed during the disease, and we were not able to determine whether there is HBV reactivation. Finally, the patients were not grouped according to chronic HBV infection stages due to the lack of HBeAg and HBV-DNA levels of some patients. 

The authors declare that there is no conflict of interest. 

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. 

HIV-hepatitis B virus coinfection: epidemiology, pathogenesis, and treatment

Evaluation of serum hepatic enzyme activities in different COVID-19 phenotypes

Risk factors of liver injury in patients with coronavirus disease 2019 in Jiangsu, China: a retrospective, multi-center study

Profiles of liver function abnormalities in elderly patients with Coronavirus Disease

Liver injury in COVID-19: management and challenges

Patients with SARS-CoV-2 and HBV co-infection are at risk of greater liver injury. Genes Dis

Effect of SARS-CoV-2 coinfection was not apparent on the dynamics of chronic hepatitis B infection

Seroprevalence of hepatitis B and C virus infections and risk factors in Turkey: a fieldwork TURHEP study

SARS-CoV-2 and the liver: considerations in hepatitis B and hepatitis C infections. Clin Liver Dis (Hoboken)

Interaction between hepatitis B virus and SARS-CoV-2 infections

Rhabdomyolysis: a review of the literature

Rhabdomyolysis as the main manifestation of coronavirus disease

Clinical characteristics and abnormal parameters evolution in patients with novel coronavirus infection: a case series of 272 cases in Guangzhou

Biomarkers associated with COVID-19 disease progression

Comparison of liver biochemical abnormality between COVID-19 patients with liver cirrhosis versus COVID-19 alone and liver cirrhosis alone A STROBE observational study

Incidence, risk factors, and prognosis of abnormal liver biochemical tests in COVID-19 patients: a systematic review and meta-analysis

Management of patients with liver derangement during the COVID-19 pandemic: an Asia-Pacific position statement

Liver injury is independently associated with adverse clinical outcomes in patients with COVID-19

A case series of COVID-19 patients with chronic hepatitis B virus infection

Clinical characteristics in patients with SARS-CoV-2/HBV co-infection

Epidemiological and clinical characteristics of 70 cases of coronavirus disease and concomitant hepatitis B virus infection: a multicentre descriptive study

Characteristics of liver function in patients with SARS-CoV-2 and chronic HBV coinfection

Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic hepatitis B virus infection

Coronavirus disease 2019 and prevalence of chronic liver disease: a meta-analysis

Effect of COVID-19 on patients with compensated chronic liver diseases

Clinical characteristics of COVID-19 patients with pre-existing hepatitis B virus infection: a multicenter report

Clinical Characteristics of hospitalized patients with SARS-CoV-2 and hepatitis B virus co-infection

Clinical features and outcomes of coronavirus disease 2019 (COVID-19) patients with chronic hepatitis B virus infection

Current and past infections of hepatitis B virus do not increase mortality in patients with COVID-19