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Corresponding author. Address: Department of Epidemiology, School of Public Health, Zhengzhou University, No. 100 of Science Avenue, Zhengzhou 450001, China. Phone: 86-371-67781248, fax: 86-371-67781248.
In the Journal of Hepatology, Ji et al. reported that the presence of non-alcoholic fatty liver disease (NAFLD) was significantly associated with an increased risk of coronavirus disease 2019 (COVID-19) progression in a multivariate model;
reported that the presence of NAFLD was not significantly associated with COVID-19 mortality, disease severity or disease progression in multivariate models. This suggests that whether the presence of NAFLD is an independent predictor of severe COVID-19 remains inconclusive. The European Association for the Study of the Liver (EASL) position in Marjot et al.’s paper noted that patients with NAFLD were at increased risk of developing severe COVID-19 which might be attributed to the presence of other high-risk comorbidities.
The literature was searched in the online databases of Web of Science, PubMed, Elsevier ScienceDirect, Wiley Library, EMBASE, Springer Link, Scopus and the Cochrane Library for all potentially eligible articles which were published between December 10, 2019 and September 7, 2022. The following keywords were used: (“NAFLD” OR “non-alcoholic fatty liver disease” OR “MAFLD” OR “metabolic associated fatty liver disease”) and (“2019-nCoV” OR “SARS-CoV-2” OR “COVID-19” OR “2019 novel coronavirus” OR “severe acute respiratory syndrome coronavirus 2” OR “coronavirus disease 2019”). The exposure group was patients with COVID-19 and NAFLD, and the control group was patients with COVID-19 without NAFLD. The outcome of interest was severe COVID-19 (which was reported as severe/critical illness, severity/progression, intensive care unit admission, need for invasive mechanical ventilation and mortality, etc. in the original articles). We included all peer-reviewed articles in English providing the risk factor-adjusted effect sizes of the association between NAFLD and severe COVID-19 using multivariate models. We excluded case reports, reviews, preprints, study protocols, editorials, commentaries, errata, and studies with unadjusted effect sizes or without available data. Two independent researchers conducted literature retrieval and data extraction. Any disagreements were settled by discussion between the researchers until consensus was achieved. In order to find additional pertinent studies, the listed references of the included studies and relevant reviews were further scanned and manually retrieved.
The Stata 11.2 software was used for statistical analyses. The pooled odds ratio (OR) and 95% confidence interval (CI) were estimated by a random-effects model.
The Cochran’s Q test and I2 test were applied to assess statistical heterogeneity. A leave-one-out sensitivity analysis was utilized to evaluate the influences of individual studies on the overall results. Publication bias was assessed by Egger’s test
Subgroup analysis was conducted by age (mean/median), male proportion and study design. p values less than 0.05 were deemed statistically significant.
A total of 18 eligible studies (22,056 cases) were included in this meta-analysis. Our results indicated that the presence of NAFLD was significantly independently associated with more severe COVID-19 based on risk factor-adjusted effect sizes (pooled OR 1.76; 95% CI 1.24-2.49; Fig. 1A). Subgroup analyses by male proportion (pooled OR 1.64; 95% CI 1.18-2.26 for ≥50% and 2.25; 95% CI 1.21-4.17 for <50%) and study design (pooled OR 1.87; 95% CI 1.22-2.88 for retrospective studies and 1.40; 95% CI 1.15-1.70 for the others) yielded consistent results. Subgroup analysis by age (mean/median) showed that the presence of NAFLD was significantly independently associated with more severe COVID-19 among younger patients (pooled OR 2.08; 95% CI 1.33-3.27 for <60 years-old; Fig. 1B), but not among older patients (pooled OR 1.37; 95% CI 0.97-1.93 for ≥60 years-old; Fig. 1C). Sensitivity analyses showed that deleting each individual study once had no significant impact on the overall results (Fig. 1D-F). Egger’s test (p = 0.003) and Begg’s test (p = 0.005) demonstrated that publication bias might exist.
Although the pooled OR was calculated on the basis of the risk factor-adjusted effects sizes (mainly adjusting for age, sex, smoking, obesity, diabetes and hypertension), other factors (such as SARS-CoV-2 variants, status of vaccination and medication)
might certainly play an important role in modifying the association between NAFLD and severe COVID-19. Unfortunately, few included studies provided this information, hence we could not assess the impact of these factors on the association between NAFLD and severe COVID-19, which should be addressed in the future when more data are available.
In conclusion, this meta-analysis of risk factor-adjusted effect sizes indicated that the presence of NAFLD was significantly independently associated with more severe COVID-19 among younger patients rather than older patients. Future well-designed studies with comprehensive measurements of potential confounding factors are warranted to verify our findings.
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.
Haiyan Yang and Guangcai Duan conceptualized the study. Ying Wang and Yadong Wang performed literature search and data extraction. Ying Wang and Yadong Wang analyzed the data. Ying Wang and Haiyan Yang 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.
We would like to thank Jie Xu, Jiahao Ren, Li Shi, Mengke Hu, Shuwen Li, Xueya Han, Ruiying Zhang, Jian Wu, Hongjie Hou, Peihua Zhang, Yang Li, Wenwei Xiao and Xuan Liang (All are from Department of Epidemiology, School of Public Health, Zhengzhou University) for their kind help in searching articles and collecting data.
The following are the supplementary data to this article: