key: cord-0971841-v3mkhb80 authors: Jayant, Kumar; Reccia, Isabella; Virdis, Francesco; Pyda, Jordan S.; Bachul, Piotr J.; di Sabato, Diego; Barth, Rolf N.; Fung, John; Baker, Talia; Witkowski, Piotr title: COVID‐19 in hospitalized liver transplant recipients: An early systematic review and meta‐analysis date: 2021-02-25 journal: Clin Transplant DOI: 10.1111/ctr.14246 sha: 3817804509d9899c037624bb2f44e1b73d58e809 doc_id: 971841 cord_uid: v3mkhb80 Adverse clinical outcomes related to SARS‐CoV‐2 infection among liver transplant (LTx) recipients remain undefined. We performed a meta‐analysis to determine the pooled prevalence of outcomes among hospitalized LTx recipients with COVID‐19. A database search of literature published between December 1, 2019, and November 20, 2020, was performed per PRISMA guidelines. Twelve studies comprising 517 hospitalized LTx recipients with COVID‐19 were analyzed. Common presenting symptoms were fever (71%), cough (62%), dyspnea (48%), and diarrhea (28%). Approximately 77% (95% CI, 61%‐93%) of LTx recipients had a history of liver cirrhosis. The most prevalent comorbidities were hypertension (55%), diabetes (45%), and cardiac disease (21%). In‐hospital mortality was 20% (95% CI, 13%‐28%) and rose to 41% (95% CI, 19%‐63%) (P < 0.00) with ICU admission. Additional subgroup analysis demonstrated a higher mortality risk in the elderly (>60‐65 years) (OR 4.26; 95% CI, 2.14‐8.49). There was no correlation in respect to sex or time since transplant. In summary, LTx recipients with COVID‐19 had a high prevalence of dyspnea and gastrointestinal symptoms. In‐hospital mortality was comparable to non‐transplant populations with similar comorbidities but appeared to be less than what is reported elsewhere for cirrhotic patients (26%‐40%). Importantly, the observed high case fatality in the elderly could be due to age‐associated comorbidities. transplant recipients owing to immune dysregulation, immunosuppressive state, and associated comorbidities. [2] [3] [4] [5] Liver transplantation has been established as a life-saving procedure for all forms of end-stage liver disease; however, in the initial phase of the global COVID-19 pandemic, most transplant centers were forced to restrict transplant activities not only due to the highly transmissible nature of the pathogen but also because of a heightened risk of severe disease in the immunocompromised individuals. 6, 7 Hence, a better understanding of the disease process in this specific cohort needs to be pursued to allow for optimal organ and patient selection for liver transplantation as well as perioperative screening and immunosuppression management. Moreover, to optimize transplant timing, such concerns ought to be balanced between the impact of a SARS-CoV-2 infection in cirrhotic patients versus liver transplant recipients. Recent reports by two international collaborative registries (ie, the COVID-Hep registry at COVID-Hep.net and the SECURE-cirrhosis registry at covidcirrhosis.web.unc.edu) included data from 103 cirrhotic patients from 18 countries. These databases reported a 95.2% hospitalization rate and overall in-house mortality of 39.8%. The studies revealed a significant association between case fatality and Child-Pugh class "C" as well as higher MELD score (model for end-stage liver disease) with a dismal prognosis and overall mortality of 63.2%. 8 In this meta-analysis, we summarize the existing literature pertaining to COVID-19 in liver transplant recipients in order to determine the impact of the pathogen in this cohort. Furthermore, we highlight reported changes in immunosuppressive regimens and attempt to identify modifiable clinical factors associated with clinical outcomes and mortality. We also reviewed the existing literature to compare the morbidity and mortality between decompensated cirrhotic patients and liver transplant recipients. The initial systematic review was performed following registration in PROSPERO, an international database of prospectively registered systematic reviews (CRD42020191699). The search strategy was formulated as per the Cochrane Handbook for Systematic Reviews and reported as per the guidelines proposed by a meta-analysis of observational studies in epidemiology (MOOSE). 9 A comprehensive electronic literature search was made using MeSH terms "COVID-19" AND "liver transplantation"; "Coronavirus" AND "liver transplantation"; "COVID-19" AND "liver transplantation" AND "mortality"; "COVID-19" AND "liver transplantation" AND "Clinical outcomes". We searched the following databases: MEDLINE, PubMed, EMBASE, MedRxiv, Cochrane, Crossref, Scopus, and clinical trial registries on November 10, 2020. Additionally, a manual search suing the free terms "2019 novel coronavirus", "SARS-CoV-2", "2019-nCoV infection" was made for preprints, case reports, abstracts, and bibliographies to identify additional eligible studies. The final search was completed on November 20, 2020, and was not restricted by language or geography. After an initial screen of titles and abstracts, the full text of identified articles was search based upon previously established inclusion criteria. All observational studies available in the form of full-text articles relating to COVID-19 in liver transplantation were reviewed. All other publications, including editorials, reviews, and letters, were also excluded. Our outcomes of interest included clinical presentation, the severity of respiratory disease, hospital admission, intensive care unit admission, the need for mechanical ventilation, the incidence of ARDS (acute respiratory distress syndrome), presence of acute kidney injury, blood levels of lymphocytes, liver enzymes, serum bilirubin and inflammatory markers, modifications of the immunosuppressive regimen, whether other treatments were administered, prognosis as related to recovery, graft rejection, and mortality as reported in the reviewed literature. Wherever possible, group-wise comparisons were made to determine mortality comparing the following factors: age (<60-65 years vs ≥60-65 years), time since LTx (<2 years vs ≥2 years), and sex (as reported). Two separate reviewers, KJ and IR, independently screened the search results using a two-stage method via a shared online platform. In the first stage, article titles and abstracts were scrutinized to exclude obviously ineligible studies. During the second stage, full texts or available limited text (eg, posters) were read and additional articles were excluded. In case of disagreement in article selection, matters were discussed until a consensus was achieved in collaboration with the senior author (PW). The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used to direct the search and study selection ( Figure 1 ). The data were extracted from the included studies and organized into a predefined data set to generate central tendency (ie, mean or median) and dispersion (ie, 95% CI, IQR, or range). Whenever means and standard deviations of the analyzed variables were not available, the values were inputted from the available statistics (ie, median, IQR, or range). 10, 11 Heterogeneity among included studies was investigated through I 2 statistics and designated as low if I 2 was ≤ 25%, moderate if 25%-75%, and high if I 2 was ≥ 75%. 12 Due to the heterogeneity within and between the studies, a random-effects model was chosen to compute the pooled prevalence (ie, effect size) with 95% confidence interval (CI). The software used for statistical analysis was STATA/SE 16 (Stata, College Station, TX). In case of a single arm "zero" event, 0.5 was added to the zero cells and the "metan" command was used. Whenever there was a "zero event" in both arms, the study was excluded from the analysis. The risk of bias for observational studies was evaluated via a quality analysis of included studies as per the guidelines suggested by the National Institutes of Health in the Quality Assessment Tool for Case Series Studies whenever applicable. 13, 14 3 | RE SULTS The primary literature search yielded a total of 83 articles matching our preliminary selection criteria. Of these, 69 were excluded as detailed in the PRISMA flowchart ( Figure 1 ). Other articles such as case reports, reviews, letters to editor, opinions, and editorials were excluded as well (Table 1) . Whenever we identified studies by the same authors containing overlapping data, only the study with highest number of cases was selected for inclusion. 15, 16 A final total of 12 observational studies were included for data extraction ( Figure 2 ). [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] The pooled estimate of reported attributes of COVID-19 in the (95% CI 46%-93%), African Americans 11% (95% CI 7%-16%), and Latinos/Hispanics 5% (95% CI 2%-8%). We assessed the prevalence of various comorbidities outlined in the included studies. Six studies, 352 COVID-19 patients, of which 42 had chronic lung disease patients with pooled prevalence of 14% (95% CI, 6%-22%). The pooled prevalence of malignancy and smoking were both 11% (Table 4 ). The pooled estimate of presenting symptoms of COVID-19 in the LTx population is presented in Table 4 . Fever was the most common with a prevalence of 71% (95% CI, 61%-81%), followed by cough in 62% (95% CI, 53%-73%). Other common manifestations were dyspnea in 48%, and gastrointestinal symptoms in 28% of patients. The pooled prevalence of pneumonia on imaging was 77% (95% CI, 69%-84%). The pooled prevalence of complications such as ARDS and respiratory status requiring mechanical ventilation was 56% (95% CI, 26%-86%) and 24% (95% CI, 12%-36%), respectively ( Figure 3A , B). The incidence of intensive care unit (ICU) admission was 22% (95%CI, 12%-32%) ( Figure 3C ). The pooled prevalence of in-hospital mortality rate was 20% (95%CI, 13%-28%) ( Figure 3D ) and was significantly lower as compared to the mortality for patients admitted to the ICU which was 41% (95% CI, 19%-63%) (P < 0.00) ( Figure 3E ). The available data from the included studies revealed that calcineurin inhibitors were used for maintenance immunosuppression in 86% (95% CI, 76%-95%) of reported patients and were withheld or reduced in 38% (95% CI, 9%-67%). Similarly, mycophenolate mofetil/ mycophenolic acid (MMF/MPA) was a part of the immunosuppressive regimen in 50% (95% CI, 44%-56%) of reported patients and modified in 60% (95% CI, 17%-90%). Additionally, 9% (95% CI, 3%-15%) of patients were on mammalian target of rapamycin inhibitors (mTORi) and of these 50% (95% CI, 25%-76%) of patients had dose modification (Table 4) . Increased doses or pulsed steroids were administered in 22% (95% CI, 13%-31%) of patients, presumably with intent to modu- hydroxychloroquine and tocilizumab was 58% (95% CI, 35%-82%) and 6% (95% CI, 1%-12%), respectively (Table 4 ). We analyzed the available mortality data in terms of age (<60- Figure 4A -C). The The findings of this systematic review and meta-analysis were based on a large number of hospitalized liver transplant recipients with diagnosis of COVID-19. The data analysis revealed a pooled hospital mortality of 20% (95% CI, 13%-28%) in LTx recipients with confirmed COVID-19 and could be secondary to the higher burden of comorbidities and was in line with the observed case fatality in the general population with similar comorbidities (11%-55%). [43] [44] [45] [46] The observed finding can also be explained because of the increasing age and age-related morbidity, which were implicated as important attributes for increased case fatality of 18.7% for patients between 60 and 69 years of age and of 35.8% for patients of 70 and 79 years of age. 47 The mortality was lower than reported among cirrhotic liver disease patients with COVID-19, for whom outlined mortality was 26%-40%; this strongly correlated with a higher Child-Pugh class and a higher MELD score. 8 infected with SARS-CoV-2, they may remain infectious for a longer duration due to higher viral titers and a prolonged replication period. 35 There are certain limitations to this meta-analysis. First, the studies we analyzed were retrospective reports which have their inherent design limitations. Second, the data were heterogenous with particularly wide variations in rates of hospitalization and ICU admission. Third, we used a random-effects model for data analysis and the results require cautious interpretation due to high heterogeneity of outcomes. Nevertheless, despite these limitations, we believe this meta-analysis can help further the understanding of the impact of COVID-19 among F I G U R E 4 A, Forest plot representing odds ratio (OR) of COVID-19 related death in liver transplant recipients in age group ≥ 60-65 years vs <60-65 years while comparing the weight of the studies in the meta-analysis. The diamond shows higher risk ≥ 60-65 year old group following analysis (red dashed line represents OR of 4.26). The edges of the blue diamond represent 95% confidence intervals (2.14-8.49). B, Forest plot representing odds ratio (OR) of COVID-19 related death in liver transplant recipients in late post-transplant period group (>2 years) in contrast to early post-transplant period (≤2 years) while comparing the weight of the studies in the meta-analysis. The diamond shows the odds ratio in late post-transplant group 3.07 and is represented by the red dotted line. The edges of the blue diamond represent 95% confidence intervals (0.65-14.46). C, Forest plot representing the proportion of COVID-19 related death in liver transplant recipients in the female population in contrast to the male population while comparing the weight of the studies in the meta-analysis. 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How to cite this article COVID-19 in hospitalized liver transplant recipients: An early systematic review and meta-analysis The data that support the findings of this study are available from the corresponding author upon reasonable request.