Invasive fungal infection before and after liver transplantation

Table 1 Studies assessing the prevalence of invasive fungal disease in patients with acute-on-chronic liver failure

Ref.	Study design	Diagnostic criteria for IFD	Prevalence of IFD	Outcome	Risk factors for IFD
Verma et al[11], 2019	Single-center, retrospective study on ICU patients from India	EORTC/MSG diagnostic criteria	39/264 (14.7%). 11 (28%) proven. 25 (64%) IC and 14 (36%) IA	In-hospital mortality 77%	Hemodialysis. Prior antibiotic use
Fernández et al[12], 2018	Multi-center, prospective study on non-ICU ACLF patients across Europe	EORTC/MSG diagnostic criteria	8/407 (1.9%). 7 (87%) IC. 1 (13%) IA	28-d and 90-d mortality 57% and 71%, respectively	NR
Theocharidou et al[13]1, 2016	Analysis from prospectively collected database on ICU patients across the United Kingdom	EORTC/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, 2013	Retrospective single center study from China on IA	EORTC/MSG diagnostic criteria	39/787 (4.9%)	Cumulative mortality 61%	Age. Hepatic encephalopathy. Steroid use
Lin et al[15]2, 2013	Single center retrospective study from non-ICU hepatitis B cirrhotic patients from China	EORTC/MSG diagnostic criteria	60/126 (47.6%). Proven IFD: 14 (23%). 9 (64%) C. Albicans 2 (14%) Criptococcus neoformans: 1 (7%) C. Tropicalis; 1 (7%) C. Glabrata; 1 (7%) IA	Cumulative mortality 40%	Hepatitis B viral load
Levesque et al[16], 2019	Single center retrospective study on ICU patients with cirrhosis and IA in France	EORTC/MSG diagnostic criteria	60/362 (16.6%). 43/60 (71.7%) fulfilled ACLF criteria. 17/60 (28%) had IA	IA associated cumulative in-hospital mortality 71%	NR

¹The manuscript did not extensively classify patients according to acute-on-chronic liver failure (ACLF) criteria.

²This study used the APASL criteria for ACLF diagnosis. Colonizations are not reported. ACLF: Acute-on-chronic liver failure; IA: Invasive aspergillosis; IC: Invasive candidiasis; IFD: Invasive fungal disease; NR: Not reported; ICU: Intensive care unit; EORTC: European Organization for Research and Treatment of Cancer; MSG: Mycoses Study Group.

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], 2013	Single-center study. LTs between 1999-2005. Effectiveness of targeted prophylaxis	Group 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 prophylaxis	High risk group (≥ 1 RF): ALF; ICU prior to LT; re-LT; re-operation	Group 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], 2013	Single-center study. LTs between 1997-2009. Comparative study for targeted prophylaxis in at-risk patients	Group 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-operation	Group 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], 2013	Single-center study. LTs between 2005-2008. Effectiveness of universal prophylaxis	Fluconazole (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], 2014	Single-center study. LTs between 2008-2011. Effectiveness of targeted prophylaxis	Group 1 (high risk): L-AmB 100 mg/d for 2 wk OR nystatin alone. Group 2 (low-risk): Nystatin	High risk (≥ 1 RF): Urgent LT; sCr > 2 mg/Dl; AKI after LT; re-LT; re-operation; transfusion of > 40 BP	Group 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], 2014	Randomized, double-blind trial. LTs between 2010-2011. Comparative trial for targeted prophylaxis	Group 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 discharge	High 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-operation	200 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], 2015	Randomized, open-label study. LTs between 2009-2012. Comparative trial for targeted prophylaxis	Group 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 patients	High 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 BP	Group 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], 2015	Prospective non-randomized trial. LTs between 2009-2013. Safety of high dose L-AmB for targeted prophylaxis	L-AmB 10 mg/Kg once a week until hospital discharge for a minimum of 2 wk	High 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], 2015	Single-center study. LTs between 2008-2012. Effectiveness of targeted prophylaxis	Universal 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 prophylaxis	Inclusion 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 LT	Universal 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], 2016	Single-center study. LTs between 2008-2014. Targeted prophylaxis against IA	Group 1: Voriconazole 200 mg BID for 90 d. Group 2: Oral nystatin OR fluconazole	High risk group: MELD score > 25. OR ≥ 2 RF: Pre-LT ICU stay > 24h; inotropic support; RRT; re-LT; Combined transplant; pre-LT mechanical ventilation; ALF	Group 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], 2016	Single-center study. LTs between 2006-2012. Comparative observational study for targeted prophylaxis	Group 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. Choledochojejunostomy	Group 1 vs Group 2: 28 vs 26 LTs. No episodes of IFD occurred in both groups
Fortún et al[56], 2016	Multicenter study. LTs between 2005-2012. Comparative observational study for targeted prophylaxis	Group 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 d	Group 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], 2016	Single-center study. LTs between 2005-2014. Effectiveness of targeted prophylaxis	Group 1: Anidulafungin (100 mg/d) OR micafungin (100 mg/d)1. Group 2: No prophylaxis	High risk patients: MELD ≥ 20	Group 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], 2016	Retrospective, single-center study. LTs between 2010-2014. Evaluation of risk factors for a targeted antifungal prophylaxis	Group 1 (no RF): No prophylaxis. Group 2 (1 RF IC): Fluconazole. Group 3 (high risk patients): Anti-mold agent	High-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-LT	303 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], 2018	Single-center study. LTs between 2011-2015. Effectiveness of targeted prophylaxis	Group 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], 2019	Single-center study. LTs between 2009-2016. Effectiveness of fixed dose prophylaxis	Group 1: Fluconazole fixed dose (400 mg/d for 14d) in at-risk patients. Group 2: Unsupervised antifungal protocols	High 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 BP	High-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], 2020	Multicenter, randomized, open-label trial. Living donor LTs 2012-2015. Comparative study for universal prophylaxis	Group 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 prophylaxis	Group 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

¹Duration of prophylaxis not reported. BP: Blood products; IA: Invasive aspergillosis; IC: Invasive candidiasis; IFD: Invasive fungal disease; L-AmB: Liposomal amphotericin B; LT: Liver transplantation; RF: Risk factor; RRT: Renal replacement therapy; sCr: Serum creatinine; ICU: Intensive care unit.