Edited by: Ang Li, First Affiliated Hospital of Zhengzhou University, China
Reviewed by: Yi Huimin, Third Affiliated Hospital of Sun Yat-sen University, China; Wei Zhang, Zhejiang University, China; Ning Li, The Second People's Hospital of ShanXi, China
This article was submitted to Gastroenterology, a section of the journal Frontiers in Medicine
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Since the first liver transplantation (LT) by Thomas Starzl in 1963, the prognosis was significantly improved. LT can be considered the most effective therapy for nearly all causes of end-stage liver diseases (ESLDs) (
Several clinical trials have shown that the causative organisms of IFIs are variable.
Many studies have reported the risk factors for IFI post-LT, including bacterial infections in the first month and absence of antifungal prophylaxis (
A literature search was performed in PubMed, Web of Science, Embase, the Cochrane Library to identify studies related to risk factors of IFI after LT that were published up to June 2020. The terms searched were “liver transplantation or hepatic transplantation or liver grafting” and “invasive fungal infection or IFI” and “risk factors”.
Studies were selected in accordance with the “Preferred reporting items for systematic reviews and meta-analyses” (PRISMA) statement (
The following were the exclusion criteria: (1) duplicate articles; (2) reviews, meeting abstracts, letters, or case reports; (3) no diagnostic or no defined criteria for IFIs; (4) studies were related to the risk factors of IFIs after the organ transplantation but did not report the relevant data on the LT subgroup; (5) studies included data of risk factors for LT infection but did not show the information for IFI.
Relevant information was extracted independently by the two reviewers (ML and LYS). A final check was confirmed by another researcher (ZJZ). The extracted data included the first author, publication year, country of origin, study time and design, number of patients and controls, and risk factors for IFIs with odds ratio (OR) and 95% CI from the multivariate analyses.
The quality of each included study was independently evaluated by the three reviewers (ML, LYS, and ZJZ) based on the Newcastle–Ottawa Scale (NOS) (
Statistical analysis was performed using Review Manager 5.3 and Stata 12.0. Heterogeneity was considered significant with
The literature search yielded 2,405 results; most studies were excluded because they were duplicate studies or because they were not relevant to our meta-analysis. Then, 84 studies were excluded after the full-text articles were reviewed because they did not match the criteria. Finally, 14 studies involving 4,284 recipients (533 cases and 3,751 controls) were included in this meta-analysis (
Flowchart of the selection process.
The specific characteristics of the studies included in the meta-analysis are presented in
Characteristics of studies included in the meta-analysis.
Ohkubo et al. ( |
2012 | Case-control | Japan | over a 6-year period | 156 | 24.5 | 46 | 19/137 | 6 points |
Eschenauer et al. ( |
2015 | Case-control | USA | November 2008 to December 2012 | 382 | 55.7 ± 10.7 | 65 | 20/362 | 6 points |
Kawagishi et al. ( |
2006 | Cohort | Japan | July 1991 to November 2005 | 96 | 18.67 | 41 | 8/88 | 7 points |
Utsumi et al. ( |
2019 | Case-control | Japan | January 2005 and April 2012 | 153 | 55 | 54 | 15/128 | 8 points |
Lavezzo et al. ( |
2017 | Case-control | Italy | January 2011 to December 2015 | 268 | NA | NA | 16/252 | 6 points |
Fortún et al. ( |
2003 | Cohort | Spain | January 1994 to December 2001 | 131 | NA | 70 | 22/109 | 8 points |
Raghuram et al. ( |
2012 | Case-control | USA | January 2003 to December2007 | 502 | 56 | 65 | 58/444 | 6 points |
Lum et al. ( |
2020 | Cohort | Australia | January 2005 to October 2015 | 554 | NA | NA | 28/56 | 7 points |
Alexander et al. ( |
2006 | Cohort | USA | January 1997 to December 1999 | 153 | 51 | 61 | 28/125 | 7 points |
Kim et al. ( |
2019 | Cohort | Korea | January 2009 and February 2012 | 482 | 53 | 76.8 | 196/286 | 7 points |
Giannella et al. ( |
2016 | Cohort | Italy | June 2010 to December 2014 | 303 | 53 | 68.6 | 19/284 | 7 points |
Jorgenson et al. ( |
2019 | Cohort | USA | July 2009 to June 2017 | 189 | 54.4 ± 9.9 | 60.4 | 50/139 | 6 points |
Zhou et al. ( |
2011 | Case-control | China | April 2008 to March 2010 | 248 | 50.14 ± 9.68 | 77.4 | 44/204 | 7 points |
Saliba et al. ( |
2013 | Case-control | France | January 1999 to December2005 | 667 | 46.8 ± 13.4 | 65.6 | 171/496 | 7 points |
The risk factors for IFI post-LT are shown in
Meta-analysis of risk factors of invasive fungal infection in recipients after liver transplantation.
Reoperation | 4 | 85/554 | 2.18[1.61,2.94] | 5.08 | <0.05 |
0.42 | 0.94 | 0% | Fixed | 0.508 |
Post-transplant dialysis | 3 | 54/673 | 2.03[1.52,2.72] | 4.75 | <0.05 |
1.08 | 0.58 | 0% | Fixed | 0.747 |
Bacterial infection | 2 | 190/633 | 1.81[1.33,2.46] | 3.79 | 0.0002 |
0.00 | 0.99 | 0% | Fixed | NA |
Live donor | 2 | 70/501 | 1.78[1.20,2.63] | 2.86 | 0.004 |
0.83 | 0.36 | 0% | Fixed | NA |
MELD score | 3 | 214/749 | 1.02[0.99,1.05] | 1.12 | 0.26 | 0.18 | 0.91 | 0% | Fixed | 0.782 |
Retransplantation | 2 | 218/395 | 2.45[1.54,3.89] | 3.78 | 0.0002 |
0.63 | 0.43 | 0% | Fixed | NA |
Fungal colonization | 2 | 254/730 | 2.60[1.99,3.42] | 6.92 | <0.05 |
0.73 | 0.39 | 0% | Fixed | NA |
Roux-en-Y anastomosis | 2 | 199/552 | 1.83[0.78,4.28] | 1.40 | 0.16 | 2.64 | 0.1 | 62% | Random | NA |
Forest plot for the association between IFI after LT and
Population attributable risk proportion was used to represent the proportion of cases in a population that was attributable to the exposed factor. The PARP of risk factors such as reoperation, posttransplant dialysis, bacterial infection, live donor, fungal colonization, and retransplantation is shown in
Population-attributable risk proportion of risk factors of invasive fungal infections in recipients after liver transplantation.
Reoperation | 2.18[1.61,2.94] | 36.1 | 29.9 |
Posttransplant dialysis | 2.03[1.52,2.72] | 8.5 | 8.1 |
Bacterial infection | 1.81[1.33,2.46] | 74.1 | 37.5 |
Live donor | 1.78[1.20,2.63] | 8.6 | 6.3 |
Retransplantation | 2.45[1.54,3.89] | 10.6 | 13.3 |
Fungal colonization | 2.60[1.99,3.42] | 14.4 | 18.7 |
Sensitivity analysis was used to evaluate the potential effect of heterogeneity conducted by eliminating one study in each turn. Sensitivity analyses manifested no significant changing of heterogeneity when one study was eliminated at a time.
Egger's test was conducted for statistical investigation to evaluate potential publication bias (
Invasive fungal infection is associated with poor outcomes in recipients with posttransplant (
According to the inclusion and exclusion criteria, we identified 14 studies enrolling 4,284 patients. In our meta-analysis, risk factors for IFI after LT included reoperation, posttransplant dialysis, bacterial infection, retransplantation, live donor, and fungal colonization. As summarized in
The pathogen composition of IFI after LT. spp, species;
Reoperation and retransplantation, which indicated a more complicated intraoperative and postoperative procedure, were risk factors for IFI. Meta-analysis showed that the risk of IFI in recipients with reoperation was 2.18 times higher than the recipients without reoperation, which was consistent with the results of previous studies (
Recipients of the live donor were at a higher risk of IFI after LT, which was consistent with the previous studies (
Our study also found that the risk of IFI increased with the posttransplant dialysis that is consistent with the studies of Ohkubo et al. (
We used PARP to estimate the percentage of IFI in recipients of LT attributed to one kind of risk factor. We found that the PARP of the bacterial infection and reoperation was high. Thus, we infer that these risk factors were important for IFI post-LT.
Fungal colonization was defined as the presence of fungus before LT without clinical symptoms or evidence of infection. We found that the patients with fungal colonization were at a higher risk of IFI. Several studies have shown that antifungal prophylaxis dramatically reduces fungal colonization, mortality caused by a fungal infection, and the overall incidence of fungal infection (
There were several limitations to this meta-analysis. First, we only included English language literature from four databases, and there may have been incomplete retrieval. Second, there may have been mistakes in the data conversion because some study data required to be recalculated. Third, because of the limitations of the included date, we did not conduct subgroup analyses and funnel plots. At last, analyses were limited by the sample size included in this meta-analysis, so the combined effect size may have been exaggerated to draw the opposite conclusion.
In conclusion, this meta-analysis identified some risk factors for IFI post-LT and might provide a basis for clinical prevention. However, a well-designed prospective cohort study should be conducted to validate our findings.
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
ML and LYS designed the study and wrote the first draft of the manuscript. ML and ZJZ verified data extraction, data analysis, and reviewed the manuscript. LYS and ZJZ supervised the data acquisition, data analysis, and interpretation. All the authors read and approved the final manuscript.
This research was supported by the Beijing Municipal Science & Technology Commission (No. Z181100001718220).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.