key: cord-0745183-880k9fpg
authors: Mirzaie, H.; Vahidi, M.; Shokoohi, M.; Darvishian, M.; Sharifi, H.; Sharafi, H.; Karamouzian, M.
title: COVID-19 AMONG PATIENTS WITH HEPATITIS B OR HEPATITIS C: A SYSTEMATIC REVIEW
date: 2020-10-23
journal: nan
DOI: 10.1101/2020.10.22.20216317
sha: 13dd6f63840f9dea7b110f57c683e99e709d8dea
doc_id: 745183
cord_uid: 880k9fpg

Background & aims: Hepatic manifestations of coronavirus disease 2019 (COVID-19) are common among people infected with hepatitis B virus (HBV) and hepatitis C virus (HCV). This systematic review aimed to summarize the evidence on COVID-19 patients with HBV or HCV co-infections. Methods: We searched multiple electronic databases and preprint servers from December 1, 2019 to August 9, 2020. Studies were included if they reported quantitative empirical data on COVID- 19 patients with HBV or HCV co-infections. Descriptive analyses were reported and data were narratively synthesized. Quality assessments was completed using the Joanna Briggs Institute critical appraisal tools. Results: Out of the 941 identified records, 28 studies were included. Of the eligible studies, 235 patients with COVID-19 were infected with HBV and 22 patients with HCV. Most patients were male and mean age was 49.8 and 62.8 in patients with HBV and HCV, respectively. Death proportion was 6% among COVID-19-HBV and 13% among COVID-19-HCV co-infected patients. Among COVID-19 patients, 34.1% and 76.2% reported at least one comorbidity besides HBV and HCV infections, mainly hypertension and diabetes mellites type 2. The most common COVID-19-related symptoms in both HBV and HCV groups were fever, cough and dyspnea. ICU admission was reported in 14.1% and 21.4% of individuals with HBV and HCV, respectively. Conclusions: Our findings suggest a considerable risk of morbidity and mortality among COVID-19 patients with HBV and HCV. Careful assessment of hepatic manifestations upon admission of patients could help improve health outcomes among COVID-19 patients with HBV or HCV coinfections.

The first case of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was diagnosed in china in December 2019 (1) . The world health organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic on March 11, 2020. As of October 19 , 2020, near the 40 million cases and more than 1,110,000 deaths had been reported worldwide (2) . A more severe disease course and a higher mortality rate have been reported in older patients, as well as those with underlying medical conditions including hypertension, asthma, diabetes mellitus, chronic lung disease, cardiovascular conditions, obesity and chronic kidney disease (3) (4) (5) (6) (7) (8) . COVID-19 clinical presentations could vary greatly but often include respiratory, gastrointestinal, renal, and neurological manifestations (9, 10) .

Recent studies have also reported COVID-19 cases presenting with hepatitis symptoms before developing respiratory symptoms (11) . While our understanding of SARS-CoV-2's pathogenesis continues to grow, initial studies suggest that the virus could lead to liver injury mainly by binding to angiotensin-converting enzyme 2 (ACE2) receptors on hepatocytes or causing an immune-mediated hepatic injury through cytokine storm activation (12) (13) (14) . Several studies suggest that COVID-19 could lead to liver injuries and elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, particularly among sever COVID-19 cases (e.g., those admitted to intensive care unit [ICU] (15) (16) (17) (18) . Abnormal liver functions among COVID-19 patients has also been associated with increased disease severity and risk of mortality (19, 20) . A recent meta-analysis of a few studies on hepatic manifestations of COVID-19 estimated the pooled prevalence of pre-existing chronic liver disease as 1.9%, pre-existing liver cirrhosis as 0.4%, HBV as 0.9%, and HCV as 0.3% (15) . While insightful, these findings are limited by small sample-sized studies conducted in China and USA during the early months of . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. ; https://doi.org/10.1101/2020. 10.22.20216317 doi: medRxiv preprint the pandemic (i.e., as late as April 2020) (15) . These findings also contradict other earlier studies that reported a significantly higher prevalence of liver complications among COVID-19 patients in China where 2-11% of COVID-19 patients had liver-related complications and up to 54% had elevated AST and ALT levels (21) . COVID-19-related hepatic complications are particularly concerning among people living with HCV, or HBV, or HBV/HCV co-infection with pre-existing liver complications (e.g., cirrhosis, liver failure, hepatocellular carcinoma) (15, 21, 22) . Considering that around 290 million and 71 million people are living with HBV and HCV, respectively (23, 24), the number of patients with SARS-CoV-2 and HBV and/or HCV co-infections are likely to increase. Therefore, improving our understanding of the hepatic manifestations and comorbidities among COVID-19 patients living with HBV, HCV, or both is of utmost importance in enhancing the care provided for this large at-risk population. In this systematic review, we aimed to review and summarize the existing literature on COVID-19 patients living with HBV or HCV infections. The findings of our review could provide information on clinical care and treatment options for COVID-19 patients with these infections.

Inclusion criteria and analytical plan were conceptualized a priori, and are documented in Open Science Framework ( https://osf.io/p4w3j/).

Following the Systematic Reviews and Meta-Analyses (PRISMA) and Peer Review of Electronic Search Strategies (25) guidelines (see supplementary file S1 for PRISMA checklist), we searched PubMed, Scopus, Web of Science, CINAHL, Embase, Google Scholar, as well as preprint databases including medRxiv and bioRxiv from December 1, 2019 to August 9, 2020.

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 23, 2020. ; https://doi.org/10.1101/2020. 10.22.20216317 doi: medRxiv preprint Search terms were combined using appropriate Boolean operators and included subject heading terms/keywords relevant to COVID-19 (e.g., SARS-CoV-2 or coronavirus disease 2019 or COVID-19 or severe acute respiratory syndrome coronavirus 2 or coronavirus infection) and

hepatitis B or C (e.g., liver fibrosis or liver cirrhosis or hepatic transplantation or liver transplant or hepatitis C or hepatitis B or HBV or HCV). Please see supplementary file S2 for our sample search strategy.

Quantitative studies of any type (i.e., case report, case series, cross-sectional, case-control, cohort, and clinical trial) that reported individual-level and/or aggregate-level data on COVID-19 patients living with HBV, HCV, or HBV-HCV-co-infection were included in this review.

Studies that combined samples of HBV/HCV-positive and HBV/HCV-negative patients were only included if they provided subgroup analyses for people living with HBV, HCV or HBV-HCV-co-infection. Studies were excluded if they did not present original empirical data or did not report any clinical data for patients. Two reviewers (HM and MV) independently screened all titles, abstracts, and full-texts. Duplicate records were excluded and disagreements were resolved by discussion or arbitration by the senior author (MK).

Data were extracted on a) study characteristics, including first author, publication date, study type, sample size, data type, and study population, b) socio-demographic characteristics, such as patients' age and sex/gender, c) HBV-and HCV-related characteristics, including cirrhosis status, liver transplantation, receiving immunosuppressive therapy, liver enzyme levels (e.g., AST, ALT, ALP and GGT), d) COVID-19-related characteristics, including symptoms and severity of COVID-19 defined as mild (i.e., no or mild pneumonia), severe (i.e., blood oxygen . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 23, 2020. ; https://doi.org/10.1101/2020.10.22.20216317 doi: medRxiv preprint saturation≤93%, dyspnea, or lung infiltrates >50% within two days], and critical (i.e., septic shock, respiratory failure, or multiple organ failures) (26) . Hospitalization, ICU admission, survival status (recovery or death), as well as non-hepatic-related comorbidities (e.g., hypertension, diabetes, cardiovascular diseases, chronic obstructive pulmonary disease [COPD], and malignancies) were also recorded.

Two reviewers (HM and MV) completed quality assessments independently, using the Joanna Briggs Institute critical appraisal tools (27) . These tools assess different items (e.g., selection bias, information bias, and confounding bias) for various study designs; nine items for case reports, ten for case series, nine for cross-sectional studies, and eleven for cohort studies.

Descriptive analyses were used for reporting results. Continuous variables were summarized as mean and standard deviation (SD). Categorical variables were summarized by frequencies and percentages. Differences in continuous and categorical variables were compared using the twotailed student's t-test and Fisher's exact test, respectively. P-values less than 0.05 were considered as statistically significant. For combining data from studies that reported aggregatelevel data with those reporting individual-level data, we weighted the aggregate-level data by the number of patients. The proportion of death among reported patients was also measured and reported. The denominator and nominator for this measure were based on patients with HBV or HCV whose COVID-19 was diagnosed and reported. We also conducted a subgroup analysis by patients' receipt of immunosuppressive medication.

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. ; https://doi.org/10.1101/2020. 10.22.20216317 doi: medRxiv preprint Out of 941 identified records, 28 studies met our inclusion criteria and were considered for data extraction. Figure 1 shows the PRISMA flow diagram and study characteristics are presented in Table 1 . Of the 28 included studies that reported some quantitative data on SARS-CoV-2 and HBV and/or HCV co-infections, 15 studies reported SARS-CoV-2 and HBV co-infection, 10 studies reported SARS-CoV-2 and HCV co-infection, and three reported both types of coinfections. With regards to their geographical location, 15 studies reported data from china, three from the US, two from Spain, two from Brazil, and the remaining six studies from Italy, Austria, Switzerland, the UK, Lithuania, and the UAE. All the included studies were observational: 11 studies were case reports, 10 were case series, and seven were cross-sectional. The majority of the included studies (n = 22) reported individual-level data, and six studies reported aggregatelevel data.

As shown in Table 1 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. ; comorbidity other than liver disease; most common comorbidities were hypertension (19.6%, 35 out of 179), diabetes mellitus type 2 (8.9%, 16 out of 179), cardiovascular diseases (4.5%, 8 out of 179) and any type of malignancy (4.5%, 8 out of 179). Among patients with SARS-CoV-2 and HCV, 76.2% (16 out of 21) reported at least one comorbidity other than liver disease; most common comorbidities were hypertension (57.1%, 12 out of 21) and diabetes mellitus type 2 (38.1%, 8 out of 21). see Table 2 for further details.

As reported in Table 2 

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. ; https://doi.org/10.1101/2020. 10.22.20216317 doi: medRxiv preprint Of all 235 reported cases of SARS-CoV-2-HBV co-infected patients, 6% (14 cases) were deceased. Information on the age of the deceased patients in this group was available for 6 of 14 patients. The mean (SD) age of deceased patients was 59.3 (13.4) years, which was higher than the mean (SD) age of all included patients estimated as 49.8 (9.7). Information on the sex of the deceased patients was available for 6 (out of 14) patients, and all of them were male. Three of 14 deceased patients were taking immunosuppressive therapy due to liver transplantation. Of all 22

reported cases of SARS-CoV-2-HCV coinfected patients, 13.6% (three people) passed away.

These three cases were 69, 71, and 79 years old. Two of them were female, and one was male.

They had more than one comorbidity and took immunosuppressive therapy due to liver transplantation.

Based on available individual data, the mean (SD) age of immunosuppressed patients was significantly higher than patients without immunosuppression (60.8 (11.7) vs 49. Death happened in 17.6% of patients with immunosuppression and 6.4% of patients without immunosuppression (P-value = 0.1). Please see Table 3 for further details.

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020.

As shown in Table 1 , quality assessment scores of the studies ranged from 5 to 7 for case reports (out of 8 possible points), 5 to 10 for the case series (out of 10 possible points) and 8 to 9 for cross-sectional (out of 9 possible points). Further details on quality assessment tools and respective scores are presented in supplementary file S3. Many studies have reported elevated liver biochemistries to be common among COVID-19 patients with and without hepatic comorbidities (32) (33) (34) . However, these findings should be interpreted with caution. First, it is unclear whether the liver damage observed among COVID-19 patients with HBV and HCV co-infections is mainly due to the adverse impact of SARS-CoV-2 on hepatic cells or patients' pre existing viral hepatitis. Second, corticosteroids that are . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. with a history of organ transplant, this finding should also be interpreted with caution when compared to the estimated 2% overall risk of mortality among COVID-19 patients (10).

Nonetheless, these findings are informative and suggest that among those who died, . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. ; https://doi.org/10.1101/2020. 10.22.20216317 doi: medRxiv preprint multimorbidity, older age, and male gender were common in comparison with all included patients.

Our findings on the impact of immunosuppression on COVID-19's severity are interesting, given the equivocal findings of different studies on the susceptibility of immunosuppressed patients to severe SARS-CoV-2 infection. While some studies assume a higher risk for immunosuppressed population due to their systemic immunocompromised status (39, 40) , others suggest immunosuppression may provide protection against hyperactivated immune response (41, 42) .

We found that the proportion of severe COVID-19 cases, admission to ICU, and proportion of death among patients with immunosuppression were higher than patients without immunosuppression; however, these differences were not statistically significant. These findings are not conclusive and should be interpreted considering the small sample size, the observational nature, the non-matched nature of the comparisons in the included studies, and the fact that these differences can be due to the immunosuppressed group's higher likelihood for being older, male, and having had organ transplants, advanced liver disease, and other extrahepatic comorbidities.

We acknowledge the limitations of our study. First, while most COVID-19 patients are asymptomatic, the available evidence which informed this review included mostly hospitalized patients and is skewed towards more severe patients often with a history of organ transplant and advanced liver disease; therefore, our findings are not generalizable to all patients living with COVID-19 and HBV or HCV co-morbidities. Second due to descriptive design of included studies and lack of comparison group we could not identify factors associated with SARS-CoV-2-HBV or HCV co-infections. Third, most of the included studies had a small sample size and without a population-based survey of patients with HBV or HCV, the accurate prevalence of COVID-19 and its manifestations among HBV or HCV subpopulations remain unknown. Lastly, . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. ; https://doi.org/10.1101/2020. 10.22.20216317 doi: medRxiv preprint given the growing nature of the pandemic and the overwhelmed healthcare systems worldwide, viral hepatitis manifestations may be under-recorded or overlooked during clinical visits and therefore, underestimate the scope of hepatic manifestations among COVID-19 with HBV and HCV co-infections.

Our findings suggest that COVID-19 patients with HBV and HCV co-infections may be at an increased risk of morbidity and mortality. Despite the limitations of the existing evidence, our review suggests that liver enzyme abnormalities and acute hepatic injuries may be common among COVID-19 patients with HBV and HCV co-infections. Therefore, these paraclinical profiles should be monitored and examined during clinical visits. While understanding the pathogenesis of SARS-CoV-2 requires further investigations, careful assessment of hepatic manifestations upon admission could help reduce the multimorbidity among HBV or HCV patients and lead to more favourable health outcomes among COVID-19 patients.

The authors did not receive any funding for this study. MK is a member of Pierre Elliott Trudeau . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. ; . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. .

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 23, 2020. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 23, 2020. ; . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 23, 2020. ;

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