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Copyright ©The Author(s) 2020.
World J Gastroenterol. Dec 21, 2020; 26(47): 7485-7496
Published online Dec 21, 2020. doi: 10.3748/wjg.v26.i47.7485
Table 1 Studies assessing the prevalence of invasive fungal disease in patients with acute-on-chronic liver failure
Ref.Study designDiagnostic criteria for IFDPrevalence of IFDOutcomeRisk factors for IFD
Verma et al[11], 2019Single-center, retrospective study on ICU patients from IndiaEORTC/MSG diagnostic criteria39/264 (14.7%). 11 (28%) proven. 25 (64%) IC and 14 (36%) IAIn-hospital mortality 77%Hemodialysis. Prior antibiotic use
Fernández et al[12], 2018Multi-center, prospective study on non-ICU ACLF patients across EuropeEORTC/MSG diagnostic criteria8/407 (1.9%). 7 (87%) IC. 1 (13%) IA28-d and 90-d mortality 57% and 71%, respectivelyNR
Theocharidou et al[13]1, 2016Analysis from prospectively collected database on ICU patients across the United KingdomEORTC/MSG diagnostic criteria (only proven IFD considered for the analysis)8/782 (1%)In-ICU and in-hospital mortality 0%NR
Chen et al[14]2, 2013Retrospective single center study from China on IAEORTC/MSG diagnostic criteria39/787 (4.9%)Cumulative mortality 61%Age. Hepatic encephalopathy. Steroid use
Lin et al[15]2, 2013Single center retrospective study from non-ICU hepatitis B cirrhotic patients from ChinaEORTC/MSG diagnostic criteria60/126 (47.6%). Proven IFD: 14 (23%). 9 (64%) C. Albicans 2 (14%) Criptococcus neoformans: 1 (7%) C. Tropicalis; 1 (7%) C. Glabrata; 1 (7%) IACumulative mortality 40%Hepatitis B viral load
Levesque et al[16], 2019Single center retrospective study on ICU patients with cirrhosis and IA in FranceEORTC/MSG diagnostic criteria60/362 (16.6%). 43/60 (71.7%) fulfilled ACLF criteria. 17/60 (28%) had IAIA associated cumulative in-hospital mortality 71%NR
Table 2 Studies published in the last 10 years on fungal prophylaxis in the liver transplantation setting
Ref.
Study design
Prophylaxis regimen
Patient selection criteria
Outcomes
Saliba et al[37], 2013Single-center study. LTs between 1999-2005. Effectiveness of targeted prophylaxisGroup 1: L-AmB (1 mg/kg/d for 1 wk, then 2.5 mg/kg/ twice a week for 3 wk) OR fluconazole (200-400 mg/d for 3 wk for those with pre-LT Candida colonization). Group 2: No prophylaxisHigh risk group (≥ 1 RF): ALF; ICU prior to LT; re-LT; re-operationGroup 1: 198 LT recipients (n.146 L-Amb, n. 50 fluconazole, n. 2 amphotericinB). Group 2: 467 LT recipients. Lower 1 yr IFD occurrence in Group 1 (17.7% vs 32.4%; P < 0.001). IA occurrence not significantly different between groups. 1 yr graft and patient survival impaired after IFD occurrence
Sun et al[47], 2013Single-center study. LTs between 1997-2009. Comparative study for targeted prophylaxis in at-risk patientsGroup 1: Amphotericin B lipid complex (5 mg/kg/d for 21 d). Group 2: Micafungin (100 mg/d for 21 d)High risk group (≥ 1 RF): Post-LT RRT; re-LT; re-operationGroup 1 vs 2: 24 vs 18 LT recipients. Similar 90d IFD occurrence (11% vs 8.3%) and 90d mortality (29.2% and 22.2%) between groups
Trudeau et al[48], 2013Single-center study. LTs between 2005-2008. Effectiveness of universal prophylaxisFluconazole (200 mg i.v./p.o. once weekly for 3 mo)High risk group (≥ 2 RF): Re-LT; sCr > 2 mg/dL or RRT within 48 h prior to LT; choledochojejunostomy; transfusion of > 40 BP; operation time > 11 h; peri-operative fungal colonization 221 LTs (18 fulfilled high risk criteria). 6 mo overall IFD occurrence equal to 4.9%. Higher IFD occurrence in high-risk patients (16.7% vs 3.4%, P = 0.03)
Antunes et al[49], 2014Single-center study. LTs between 2008-2011. Effectiveness of targeted prophylaxisGroup 1 (high risk): L-AmB 100 mg/d for 2 wk OR nystatin alone. Group 2 (low-risk): NystatinHigh risk (≥ 1 RF): Urgent LT; sCr > 2 mg/Dl; AKI after LT; re-LT; re-operation; transfusion of > 40 BPGroup 1 vs Group 2: 104 vs 357 LT recipients. 66 (63%) patients belonging to group 1 received L-AmB prophylaxis. Cumulative 3-mo IFD occurrence 2.5%. Higher IFD occurrence in high-risk patients who didn’t receive L-AmB prophylaxis (4.5% vs 13%, P = 0.01)
Winston et al[50], 2014Randomized, double-blind trial. LTs between 2010-2011. Comparative trial for targeted prophylaxisGroup 1: Anidulafungin (200 mg/d loading those, then 100 mg/d) for 3 wk or until discharge. Group 2: fluconazole (400 mg/d, adjusted according renal function) for 3 wk or until dischargeHigh risk group (≥ 1 RF): Re-LT; ALF; Steroids for at least 2 wk before LT; ICU stay > 48 h. Colonization with Candida (> 2 sites) within 4 wk before LT; transfusion of ≥ 15 BP; operative time > 6 h; RRT at the time or within 7 d of LT; re-operation200 patients 1:1 randomized. Similar cumulative IFD occurrence between cohorts (5.1% vs 8%, P = 0.4). Equal 3 mo post-LT mortality (12% each arm). 0% IFD related deaths
Saliba et al[51], 2015Randomized, open-label study. LTs between 2009-2012. Comparative trial for targeted prophylaxisGroup 1: Micafungin (100 mg/d for 21 d or until discharge) in high risk patients. Group 2: Center-specific standard care (fluconazole 200–400 mg/d OR L-AmB 1–3 mg/kg/d OR caspofungin 70 mg loading dose followed by 50 mg/d) in high risk patientsHigh risk patients (≥ 1 RF): Re-LT; ALF; Pre- or post-operative sCr clearance ≤ 40 mL/min) or RRT; ICU 48 h prior to LT; re-operation within 5d of LT; choledochojejunostomy; peri-operative Candida colonization (≥ 2 positive cultures); prolonged mechanical ventilation > 48 h after LT; transfusion of ≥ 20 BPGroup 1 vs Group 2: 174 vs 173 LT recipients (140 and 137 LT completed the study in each arm). Micafungin was non inferior to standard of care (composite primary and secondary efficacy endpoints)
Giannella et al[52], 2015Prospective non-randomized trial. LTs between 2009-2013. Safety of high dose L-AmB for targeted prophylaxisL-AmB 10 mg/Kg once a week until hospital discharge for a minimum of 2 wkHigh risk for IC (≥ 2 RF): ICU in 90d prior LT; perioperative Candida colonization; Choledochojejunostomy; transfusion of > 40 BP; AKI; rejection within 2 wk after LT; CMV DNA > 100.000 copies/mL; prolonged or repeated operation. High risk for IA (≥ 1 RF): ALF; steroid treatment before LT; multivisceral transplant; RRT; rejection; re-LT; re-operation 76 patients enrolled (39 having ≥ 2 RF for IC; 37 having ≥ 1 RF for IA). 10 patients discontinued therapy (6 for L-AmB related adverse events; 4 for IFD). 2 episodes of proven IC occurred
Eschenauer et al[53], 2015Single-center study. LTs between 2008-2012. Effectiveness of targeted prophylaxisUniversal prophylaxis (LTs between 2008-2010): Voriconazole 200 mg BID. Targeted prophylaxis (LTs between 2010-2012): Group 1: Voriconazole 200 mg BID for 30 d. Group 2: Fluconazole 400 mg/d during post-LT ICU stay. Group 3: No prophylaxisInclusion criteria for Group 1 (≥ 1 RF): re-LT; ALF; RRT; re-operation within 30 d after LT. Inclusion criteria for Group 2 (≥ 1 RF): Choledochojejunostomy; transfusion of > 40 BP and operation time ≥ 11 h; candida colonization or infection within 3 mo before LTUniversal prophylaxis: 236 LTs. Targeted prophylaxis: 145 LTs (group 1 vs 2 vs 3: 78 vs 11 vs 55). Cumulative IFD occurrence 5.2% (targeted vs universal group: 6.9% vs 4.2%; P = 0.34). 40% breakthrough IFD. Similar 100-d mortality between targeted and universal prophylaxis group
Balogh et al[54], 2016Single-center study. LTs between 2008-2014. Targeted prophylaxis against IAGroup 1: Voriconazole 200 mg BID for 90 d. Group 2: Oral nystatin OR fluconazoleHigh risk group: MELD score > 25. OR ≥ 2 RF: Pre-LT ICU stay > 24h; inotropic support; RRT; re-LT; Combined transplant; pre-LT mechanical ventilation; ALFGroup 1 vs Group 2: 174 vs 140 LT recipients; no episodes of IA occurred; no difference in graft and patient survival curves between cohorts
Perrella et al[55], 2016Single-center study. LTs between 2006-2012. Comparative observational study for targeted prophylaxisGroup 1: L-AmB (3 mg/kg/d). Group 2: Caspofungin (70 mg/d loading dose, then 50 mg/d)High risk patients (≥ 3 RF): sCr clearance < 30 mL/min and/or sCr > 4 mg/mL. Pre-LT Candida colonization. Pre-LT antibiotic use > 10 d. Pre-LT hospitalization > 7 d. Operation time ≥ 9 h. Warm ischemia ≥ 45’. Re-LT. Transfusion of > 14 BP. CholedochojejunostomyGroup 1 vs Group 2: 28 vs 26 LTs. No episodes of IFD occurred in both groups
Fortún et al[56], 2016Multicenter study. LTs between 2005-2012. Comparative observational study for targeted prophylaxisGroup 1: Caspofugin (50 mg/d). Group 2: Fluconazole 100-400 mg/d (median 200 mg/d)High risk group (≥ 1 RF): Re-LT; RRT within 30 d; LT for ALF. OR ≥ 2 of the following RF: Transfusion of ≥ 20 BP; Choledochojejunostomy; Peri-operative Candida colonization (≥ 2 sites); re-operation within 7 dGroup 1 vs Group 2: 97 vs 98 LT recipients. Median prophylaxis duration: 22 and 24 d, respectively. Similar 6-mo IFD occurrence (5.2% vs 12.2%). Reduced risk of IA in LT recipients receiving caspofungin. Similar overall mortality and IFD-related mortality between groups
Chen et al[57], 2016Single-center study. LTs between 2005-2014. Effectiveness of targeted prophylaxisGroup 1: Anidulafungin (100 mg/d) OR micafungin (100 mg/d)1. Group 2: No prophylaxisHigh risk patients: MELD ≥ 20Group 1 vs 2: 201 vs 201 LT recipients (propensity score matching). Similar IFD occurrence (11.2% vs 18.9%, P = 0.052). Lower cumulative mortality in Group 1 (23.4% vs 40.8%, P = 0.001)
Giannella et al[35], 2016Retrospective, single-center study. LTs between 2010-2014. Evaluation of risk factors for a targeted antifungal prophylaxisGroup 1 (no RF): No prophylaxis. Group 2 (1 RF IC): Fluconazole. Group 3 (high risk patients): Anti-mold agentHigh-risk patients for IC (≥ 2 RF): Prolonged operation; choledochojejunostomy; Pre-LT Candida colonization; re-LT; AKI. High-risk patients for IA (≥ 1 RF): ALF; RRT after LT; re-operation; re-LT303 patients evaluated (Groups 1 vs 2 vs 3: 91 vs 61 vs 151). Antifungal prophylaxis administered to 45.9% patients (80 L-AmB; 18 caspofungin; 41 fluconazole). Cumulative IFD prevalence 6.3%. Fluconazole prophylaxis independently associated with IFD development.
Lavezzo et al[58], 2018Single-center study. LTs between 2011-2015. Effectiveness of targeted prophylaxisGroup 1 (high risk): Amphotericin B lipid complex (3 mg/kg/d) OR L-AmB (2 mg/kg/d), for 5 to 10 d after LT. Group 2 (low risk): No prophylaxis High-risk group (≥ 1 RF): Hospitalization at LT or in the 30 d prior LT for infection; ALF; Primary-non-function; Steroid treatment at LT; sCr > 2 mg/dl before LT; RRT before or after LT; MELD > 30 at LT; re-LT, split liver, combined transplantation; Transfusion of ≥ 20 BP; choledochojejunostomy; re-operation; thymoglobulin therapy; positive fungal culture of donor preservation fluid Overall IFD prevalence 2.8% (all in the targeted prophylaxis group). 1 yr mortality higher in prophylaxis group (12.5% vs 1.8%, P = 0.001). 1-yr mortality higher in IFD patients (33.3% vs 6.4%; P < 0.001)
Jorgenson et al[59], 2019Single-center study. LTs between 2009-2016. Effectiveness of fixed dose prophylaxisGroup 1: Fluconazole fixed dose (400 mg/d for 14d) in at-risk patients. Group 2: Unsupervised antifungal protocolsHigh risk group (≥ 1 RF): Operation time > 10 h; re-operation within 30 d; re-LT; Pre LT dialysis; pre-LT Candida colonization; pre-LT hospitalization > 7 d; Choledochojejunostomy; MELD ≥ 35; transfusion ≥ 40 BPHigh-risk patients: Group 1 vs Group 2: 50 vs 139. Reduction of 1-yr IFD among high-risk cohorts (12.5% vs 26.6%). Similar 1 yr patient and graft survival
Kang et al[60], 2020Multicenter, randomized, open-label trial. Living donor LTs 2012-2015. Comparative study for universal prophylaxisGroup 1: Micafungin (100 mg/d for 3 wk or until hospital discharge). Group 2: Fluconazole (100-200 mg/d for 3 wk or until hospital discharge)Universal prophylaxisGroup 1 vs Group 2: 69 vs 75 LT recipients. IFD occurrence within 3 wk: 1/69 vs 0/75. Micafungin was non-inferior to fluconazole