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Cirrhosis is an independent predictor for COVID-19 mortality: A meta-analysis of confounding cofactors-controlled data

Published:September 26, 2022DOI:https://doi.org/10.1016/j.jhep.2022.09.015

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      To the Editor:
      We read with great interest the excellent paper by Marjot et al. titled “Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study”.
      • Marjot T.
      • Moon A.M.
      • Cook J.A.
      • Abd-Elsalam S.
      • Aloman C.
      • Armstrong M.J.
      • et al.
      Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study.
      In this paper, the authors reported that cirrhosis was significantly associated with coronavirus disease 2019 (COVID-19) mortality on multivariable analysis. Meanwhile, other studies have reported that cirrhosis is not significantly associated with the risk for COVID-19 mortality on multivariable analysis.
      • Bushman D.
      • Davidson A.
      • Pathela P.
      • Greene S.K.
      • Weiss D.
      • Reddy V.
      • et al.
      Risk factors for death among hospitalized patients aged 21-64 Years diagnosed with COVID-19-New York city, March 13–April 9, 2020.
      • Calderon-Parra J.
      • Cuervas-Mons V.
      • Moreno-Torres V.
      • Rubio-Rivas M.
      • Blas P.A.
      • Pinilla-Llorente B.
      • et al.
      Influence of chronic use of corticosteroids and calcineurin inhibitors on COVID-19 clinical outcomes: analysis of a nationwide registry.
      • Castilla J.
      • Guevara M.
      • Miqueleiz A.
      • Baigorria F.
      • Ibero-Esparza C.
      • Navascues A.
      • et al.
      Risk factors of infection, hospitalization and death from SARS-CoV-2: a population-based cohort study.
      This suggested that the association between cirrhosis and COVID-19 mortality remains inconclusive. Therefore, we performed this meta-analysis to clarify the association between cirrhosis and COVID-19 mortality based on confounding cofactors-controlled effect estimates.
      A systematic search was performed in PubMed, Web of Science, EMBASE, Springer Link, Wiley Library, Elsevier ScienceDirect and Cochrane Library to identify all relevant studies as of August 12, 2022. The search terms were: “coronavirus disease 2019”, “COVID-19”, “severe acute respiratory syndrome coronavirus 2”, “SARS-CoV-2”, “mortality”, “cirrhosis” and “liver cirrhosis”. We included the articles reporting the confounding cofactors-controlled effect estimates on the association between cirrhosis and COVID-19 mortality. We excluded preprints, reviews, duplications, errata, case reports and studies reporting the confounding cofactors-uncontrolled effect estimates. We also examined the reference lists of reviews and retrieved original literature to identify all relevant articles. Two authors independently performed literature search and data extraction. Any discrepancy was resolved by consulting the third author. This meta-analysis was reported following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      Heterogeneity was assessed by using the I2 statistic and Cochran’s Q test. The pooled effects and 95% CIs were estimated using a random-effect model. Publication bias was evaluated by Begg’s test. Sensitivity analysis, subgroup analysis and meta-regression were also performed. All statistical analyses were conducted by Stata 11.2 software. p <0.05 was considered statistically significant.
      We included 29 articles including data on 6,872,587 individuals with COVID-19. Our meta-analysis indicated that individuals with COVID-19 and cirrhosis had a significantly increased risk of mortality compared to those without cirrhosis based on confounding cofactors-controlled effect estimates (pooled effect = 1.64, 95% CI 1.37–1.96; Fig. 1A). Sensitivity analysis indicated our results were robust (Fig. 1B). We observed consistent results in the subgroup analyses by age (pooled effect = 2.10, 95% CI 1.47–2.99 for age <60, and pooled effect = 1.33, 95% CI 1.17–1.50 for age ≥60), proportion of males (pooled effect = 2.00, 95% CI 1.32–3.04 for proportion of males <50%, and pooled effect = 1.52, 95% CI 1.29–1.80 for proportion of males ≥50%), sample size (pooled effect = 1.86, 95% CI 1.26–2.75 for <3,000 cases, and pooled effect = 1.57, 95% CI 1.24–1.99 for ≥3,000 cases), study design (pooled effect = 1.46, 95% CI 1.25–1.71 for retrospective study, and pooled effect = 1.89, 95% CI 1.32-2.69 for prospective study) and setting (pooled effect = 1.42, 95% CI 1.23–1.64 for studies with all patients, and pooled effect = 1.76, 95% CI 1.27–2.45 for studies with hospitalized patients). Meta-regression indicated that no tested factors contributed to heterogeneity (age, p = 0.068; proportion of males, p = 0.093; sample size, p = 0.459; study design, p = 0.676; setting, p = 0.217). Begg’s test indicated that there was no publication bias in this meta-analysis (p = 0.138).
      Figure thumbnail gr1
      Fig. 1Forest plots of pooled effect size and sensitivity analysis of the association between cirrhosis and COVID-19 mortality.
      (A) Forest plot presenting the pooled effect size on the association between cirrhosis and COVID-19 mortality, on the basis of confounding cofactors-controlled data, ∗indicates combined effects based on subgroups; (B) A sensitivity analysis (based on omitting a single study each time) showed that our results were stable and robust.
      Cirrhosis is the end stage of many chronic liver diseases.
      • Niehaus C.E.
      • Strunz B.
      • Cornillet M.
      • Falk C.S.
      • Schnieders A.
      • Maasoumy B.
      • et al.
      MAIT cells are enriched and highly functional in ascites of patients with decompensated liver cirrhosis.
      Immune dysfunction associated with cirrhosis and fragile physiological buffering may increase susceptibility to severe COVID-19, meanwhile, SARS-CoV-2 infection can precipitate new or worsening acute hepatic decompensation and acute-on-chronic liver failure in individuals with cirrhosis, leading to adverse outcomes.
      • Marjot T.
      • Eberhardt C.S.
      • Boettler T.
      • Belli L.S.
      • Berenguer M.
      • Buti M.
      • et al.
      Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: an updated EASL position paper.
      This is consistent with our study showing that cirrhosis was an independent predictor of COVID-19 mortality. But this is a very superficial view, as other factors
      • Krassenburg L.A.P.
      • Maan R.
      • Ramji A.
      • Manns M.P.
      • Cornberg M.
      • Wedemeyer H.
      • et al.
      Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity.
      • Cornberg M.
      • Buti M.
      • Eberhardt C.S.
      • Grossi P.A.
      • Shouval D.
      EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients.
      • Cornberg M.
      • Eberhardt C.S.
      Protected or not protected, that is the question - first data on COVID-19 vaccine responses in patients with NAFLD and liver transplant recipients.
      will certainly play a role. The stage of cirrhosis (e.g., Child-Pugh and model for end-stage liver disease [MELD] score) is as important as the pandemic itself (the impact of the different SARS-CoV-2 variants and the impact of vaccination also play a role). Unfortunately, of the studies we included, only five studies described the stage of cirrhosis at baseline by different methods such as Child-Pugh score, MELD score, and chronic liver failure organ failure (CLIF-OF) score, etc. Few included studies addressed the effects of different SARS-CoV-2 variants and vaccination on the association between cirrhosis and COVID-19 mortality. Thus, limited data prevented us from performing further analysis.
      In conclusion, this meta-analysis based on confounding cofactors-controlled data indicated that cirrhosis was an independent predictor for COVID-19 mortality. The analysis confirmed what the recent EASL position paper noted.
      • Marjot T.
      • Eberhardt C.S.
      • Boettler T.
      • Belli L.S.
      • Berenguer M.
      • Buti M.
      • et al.
      Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: an updated EASL position paper.
      Further well-designed studies based on prospective study estimates are warranted to confirm our findings. We hope that the data from this quantitative meta-analysis will contribute to more accurate elaboration and substantiation of the study by Marjot et al.
      • Marjot T.
      • Moon A.M.
      • Cook J.A.
      • Abd-Elsalam S.
      • Aloman C.
      • Armstrong M.J.
      • et al.
      Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      All authors report that they have no potential conflicts of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      Haiyan Yang conceptualized the study. Ying Wang and Mengke Hu performed literature search and data extraction. Ying Wang analyzed the data. Ying Wang and Mengke Hu wrote the manuscript. All the authors approved the final manuscript.

      Data availability statement

      The data that support the findings of this study are included in this article and available from the corresponding author upon reasonable request.

      Acknowledgements

      We would like to thank Xueya Han, Shuwen Li, Ruiying Zhang, Jiahao Ren, Hongjie Hou, Peihua Zhang, Yang Li, Jian Wu, Xuan Liang, Wenwei Xiao, Jie Xu and Li Shi (All are from Department of Epidemiology, School of Public Health, Zhengzhou University) for their kind help in searching articles and collecting data, and valuable suggestions for analyzing data.

      Supplementary data

      The following are the supplementary data to this article:

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