key: cord-260993-udajtsmm authors: Youssef, Mohanad; Hussein, Mohammad; Attia, Abdallah S; Elshazli, Rami; Omar, Mahmoud; Zora, Ghassan; Farhoud, Ashraf; Elnahla, Ahmad; Shihabi, Areej; Toraih, Eman; Fawzy, Manal; Kandil, Emad title: COVID‐19 and Liver Dysfunction: a systematic review and meta‐analysis of retrospective studies date: 2020-05-23 journal: J Med Virol DOI: 10.1002/jmv.26055 sha: doc_id: 260993 cord_uid: udajtsmm BACKGROUND: Recently, Coronavirus Disease 2019 (COVID‐19) pandemic is the most significant global health crisis. In this study, we conducted a meta‐analysis to find the association between liver injuries and the severity of COVID‐19 disease. METHODS: Online databases, including PubMed, Web of Science, Scopus, and Science direct, were searched to detect relevant publications up to April 16, 2020. Depending on the heterogeneity between studies, a fixed‐ or random‐effects model was applied to pool data. Publication bias Egger's test was also performed. RESULTS: Meta‐analysis of 20 retrospective studies (3428 patients), identified that patients with a severe manifestation of COVID‐19 exhibited significantly higher levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin values with prolonged prothrombin time. Furthermore, lower albumin level was associated with a severe presentation of COVID‐19. CONCLUSION: Liver dysfunction was associated with a severe outcome of COVID‐19 disease. Close monitoring of the occurrence of liver dysfunction is beneficial in early warning of unfavorable outcomes. This article is protected by copyright. All rights reserved. Data extraction was conducted by four authors (MY, GZ, AA, and AF). The process included using a two-step approach: firstly, we screened titles and abstracts for eligibility according to the study objective, and secondly, we screened the full-text article of relevant abstracts. The Newcastle-Ottawa Scale was used for assessing the quality of eligible manuscripts. Publication bias was assessed with the Newcastle-Ottawa Quality Assessment Scale cohort studies. 17 The pooled estimates were extracted using RevMan version 5.3. Descriptive summary statistics in the form of mean, standard deviation, and range for continuous parametric measures were tabulated. Pairwise comparison between mild and severe COVID-19 patients was performed. Overall pooled odds ratio (OR) or standardized mean difference (SMD) with 95% confidence intervals (CI) were estimated for categorical Accepted Article and quantitative variables, respectively. A Fixed-effects model was employed unless significant heterogeneity was detected. In this case, the Random-effects model has applied. 18 Heterogeneity was considered significant if the I-square value exceeds 50%, or its p-value was less than 0.1. Subgroup analyses by the location of the patients, publication date, sample size, and quality score were performed. Sensitivity analysis was carried out by removing one study each time, to reflect its effect size on the overall OR. Publication bias was assessed via Begg's funnel plot and Egger's linear regression approach using Comprehensive Meta-analysis software. 19 An asymmetric funnelshape or a p-value <0.1 indicated significant bias. 20 Meta-regression analysis was employed using OpenMeta Analyst software, taking into consideration the following study characteristics; sample size, mean age of patients, percentage of males, city of the hospital, publication date, and quality score. To evaluate the reliability of statistical appraisal of this meta-analysis study, we used TSA software (version 0.9.5.10 beta) by merging several available sample sizes of applicable studies with the threshold of statistical influence to reduce the unintentional miscalculations and improve the strength of anticipations. We used twoside trials and type I error with a calculated power of 5% and 80%. If the cumulative Z-curve crosses the monitoring boundaries, no additional trials would be required. On the contrary, if the Z-curve did not accomplish the boundary levels, the necessary threshold requires additional records to achieve a prominent significance. This article is protected by copyright. All rights reserved. Following the removal of duplicates (n=1,870), our database search identified 2,582 unique citations, of which 186 full-text articles were assessed. A total of 20 eligible retrospective cohort studies, including 3428 positively confirmed COVID-19 patients, were enrolled in the current meta-analysis. The workflow of the process of study selection is demonstrated in Figure 1 . All articles were published during the period between January 30 and April 16, 2020. Most of them were from Wuhan city (13), three from Zhejiang, one from Guangdong, one from Hubei, one from Guangdong, and one from Anhui. As depicted in Table 1 , the sample size of studies ranged from 21 to 651 cohorts. The mean age of patients was 53.8 years, and 57.8% were men. In the included studies, the severe disease was detected in 36.2% of patients and the average survival rate was 72.18%. All studies except for three scored more than five on the scale. Two studies scored a three, and one study scored a two. (Figure S1 ). Apart from ALT data, significant heterogeneity was detected in laboratory results. Subgroup analysis by the origin of the hospital, publication date, sample size, and quality score of the studies failed to resolve the obvious heterogeneity. This article is protected by copyright. All rights reserved. Figure S2 ). Apart of cardiovascular disease, homogeneity between studies was detected. A total of 17 studies reported treatment to be administered to COVID-19 patients. On comparison between the two groups, severe patients were nearly three times more likely to receive steroids (OR = 3.17, 95%CI = 3.02-4.97, p <0.001) and immunoglobulins (OR = 2.75, 95%CI = 1.09-6.94, p = 0.032). Sensitivity analysis revealed that the studies of Wang 31 and Zhang 24 contributed in the significant heterogeneity observed in treatment results ( Table 2) . Figure S3 ). Considerable heterogeneity was observed for the outcomes. Meta-regression analysis for study characteristics showed higher odds of mortality in articles involving Wuhun hospitals (coefficient = 4.30, 95%CI = 3.07-5.54, p <0.001) (Supporting Information Materials Table S1 ). The funnel plot of laboratory and clinical parameters is shown in Figure S4 . Egger's test showed no publication bias for all variables (p >0.1) except for two; cardiovascular and cerebrovascular diseases (p = 0.061 and 0.041) ( Table 2) . We applied TSA on mortality rate available among all eligible articles of COVID-19 patients with a mild and severe exhibition and indicated that the cumulative Z-curve transverses the monitoring boundaries before reaching the required sample size and achieving considerable significant and so no further studies are necessary (Figure 2 ). Our meta-analysis including 3428 subjects from 20 retrospective studies explored the potential relationship between liver injury and the severity of COVID-19 disease. We found that liver dysfunction seemed to be higher in patients with severe outcomes from COVID-19 infection. Our results were in agreement with a previous study review. 21 Previously, liver injury has been reported as an important risk factor for severe outcome and death in SARS Accepted Article and Middle East Respiratory Syndrome. [22] [23] [24] [25] Patients in our study who had severe presentations of COVID-19 disease had higher levels of AST, ALT, bilirubin, and lower albumin levels. Our results are consistent with recent studies on COVID-19 disease that showed that the incidence of liver injury ranged from 58% to 78%, mainly indicated by elevated AST, ALT, and total bilirubin levels accompanied by slightly decreased albumin levels. 26, 27 In a recent study, Guan et al. documented that higher serum levels of AST were observed in nearly 18% of patients with non-severe COVID-19 disease and approximately 56% of patients with severe COVID-19 infection. 28 Moreover, in that study, higher serum levels of ALT were also observed in nearly 20% of patients with non-severe COVID-19 presentation, and approximately 28% of patients with severe COVID manifestation. 28 Similar findings in Huang et al. were also observed, where patients with severe COVID-19 features had an increased incidence of liver injury. Postmortem liver biopsies specimens were observed in deceased COVID-19 patients. The findings showed mild lobular and portal activity along with microvascular stenosis, indicating the injury could have been caused by either COVID-19 disease or drug-induced liver injury. 3 Similar to the treatment of SARS, steroids, antivirals, and antibiotics are widely used for the treatment of COVID-19. [29] [30] [31] These drugs are all potential causes of liver injury during COVID-19 treatment but have not yet been evident. 32 A recent study reported that the liver injury observed in COVID-19 patients might be caused by lopinavir, which is used as an antiviral for the treatment of SARS-CoV-2 infection. 33 It is worth noting that the specific underlying causes of liver injury and elevated levels of liver enzymes in COVID-19 patients are still limited. However, collectively the proposed mechanisms might include "hyperactivated immune This article is protected by copyright. All rights reserved. responses and cytokine storm-related systemic inflammation, psychological stress, drug toxicity, and progression of pre-existing liver diseases" as detailed by Li and Fan. 46 Further studies are needed to investigate the mechanisms of liver dysfunction in COVID-19 disease as a direct outcome of infection and the possible effects that treatment has on the liver. Limitations of our study include the following; Firstly, all the studies included in this meta-analysis used a case-control or cohort design, which are susceptible to recall and selection biases. Secondly, we could not distinguish if the liver dysfunction in COVID-19 patients was an acute liver injury or exacerbated chronic liver disease. Lastly, the enrolled studies focused on Chinese patients, which restricted a more precise estimation of liver dysfunction in the context of other races. In this meta-analysis, we comprehensively analyzed liver dysfunction in accordance with the severity of clinical outcomes in COVID-19 patients. Liver dysfunction was associated with severe COVID-19 infection. Patients presented with abnormal liver function tests are at higher risk of severe clinical outcomes. Close monitoring of the presence of liver dysfunction may be beneficial as an early indicator of worse outcomes. This may serve to better prepare the treatment of patients. None. This article is protected by copyright. All rights reserved. All authors declare no conflict of interest. This article is protected by copyright. All rights reserved. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Coronavirus disease 2019 (COVID-19) Situation Report -84. 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