Fungal infections following liver transplantation

Table 1 Common clinical manifestations of invasive fungal infection

	Clinical manifestations
Candida	Intra-abdominal abscesses
	Recurrent cholangitis
	Peritonitis
	Fungemia
Aspergillus	Invasive pulmonary Aspergillosis
	Brain abscess
	Endophthalmitis
	Osteomyelitis
	Endocarditis
Cryptococcus	CNS infection
	Focal lesions on imaging
	Meningeal enhancement

CNS: Central nervous system.

Table 2 Risk factors for invasive fungal infections

	Risk factors
Pre-operative	SBP prophylaxis with fluoroquinolone
Operative	Retransplantation
	Long transplantation time
	Long transplantation time
	Class 2 partial or complete match
	Donor from male
Post-operative	Post-transplant HD
	High number of RBC units transfused
	Post-transplant bacterial infection
	Cytomegalovirus infection
	Use of muromonab-CD3
	Aspergillus antigenemia

SBP: Spontaneous bacterial prophylaxis; HD: Hemodialysis; RBC: Red blood cells.

Table 3 Effectiveness of antifungal prophylaxis in liver transplant

Ref.	Trials	Patients	Regimens	Infection reduction	Comments
				(95%CI)
Cruciani et al[25], 2006	6	698	AmB vs Pla (1)	Total proven fungal infections RR 0.31 (0.21-0.46), IFI RR 0.33 (0.18-0.59)	Patients receiving prophylaxis had higher number of non-Albicans proven fungal infections. Mostly C. glabrata.
			Flu vs nonsystemic AF (1)
			Flu vs Pla (2)
			Itra vs Pla(1)
			Amb-Itra vs Flu-itra vs Pla (1)
Playford et al[24], 2006	7	793	Flu vs Pla (2)	Proven IFI RR 0.39 (0.18-0.85), fungal colonization RR 0.51 (0.41-0.62), fungal colonization with C. glabrata/C. krusei, RR 1.57 (0.76-3.24)	Formulated algorithm in which patients with < 2 RF deemed low risk (4%incidence) for IFI and those with ≥ 2 at high risk (25% incidence) for IFI.
			Flu vs nonsystemic AF (2)
			Itra vs Pla (2)
			AmB vs Pla (1)
Evans et al[26], 2014	14	1633	Flu vs Pla/nonabs AF (4)	Proven IFI OR 0.37 (0.19-0.72), P = 0.003, Bayesian MTC, AmB vs Pla OR 0.21 (0.05-0.71), Flu vs Pla OR 0.21 (0.06-0.57)	Benefit of AmB is of similar magnitude to that previously described for fluconazole.
			Itra vs Pla (1)
			AmB vs Pla (1)
			3 arm study with Pla/AmB/Flu (1)
			Flu vs AmB (3)
			Liposomal + Flu vs standard AmB + Flu
			Itra vs Flu (2)
			Micafungin vs standard care (1)
			Clo vs Nys (1)

AmB: Amphotericin-B; Pla: Placebo; Flu: Fluconazole; AF: Antifungal; Itra: Itraconazole; Nonabs AF: Nonabsorbable antifungal; Nys: Nystatin; Clo: Clotrimazole.

Table 4 Studies since 2014 (after the last meta-analysis) on prophylaxis for liver transplant

Ref.	Design	Regimen	Outcomes
Antunes et al[29], 2014	Single center. Retrospective (n = 461)	High risk group: AmB vs nystatin; Low risk group: nystatin	Higher IFI in high risk patients who did not receive AmB
Winston et al[30], 2014	Randomized, double-blind. 2010-2011 (n = 200)	Group 1: Andulafugin; Group 2: Flu	1:1 randomized. Similar cumulative IFI occurrence and equal 3 mo mortality
Saliba et al[27], 2015	Randomized, open label. 2009-2012 (n = 347)	Micafungin vs center specific standard care (Flu/AmB/Caspo)	Micafungin was non-inferior to standard of care
Giannella et al[31], 2015	Prospective, non-randomized. 2009-2013. Safety of high dose AmB (n = 76)	Amb 10 mg/kg Q weekly until hospital discharge for a minimum of 2 wk	10 patients discontinued therapy. (6 for AmB related AEs and 4 for IFI)
Eschenauer et al[12], 2015	Single center study. 2008-2012. Effectiveness of targeted prophylaxis (n = 381)	Universal ppx: Vori. Targeted: Group1: Vori, 30 d. Group 2: Flu during icu sta. Group3: No ppx	Cumulative IFI occurrence 5.2% (targeted vs universal group). Similar 100 day mortality between targeted and universal ppx gp. 40% breakthrough IFI
Balogh et al[32], 2016	Single center study. 2008-2014 (n = 314)	Voriconazole vs oral nystatin or Flu	No episodes of IA occurred. No difference in graft and patient survival curves between the two groups
Perrella et al[33], 2016	Single center study. 2006-2012. Comparative observational study for targeted prophylaxis (n = 54)	Group 1: AmB 3 mg/kg/day; Group2: Caspofungin 70 mg loading→50 mg/day	No episodes of IFI in both groups
Fortún et al[28], 2016	Multicenter. 2005-2012. Comparative observational study for targeted prophylaxis (n = 195)	Group 1: Caspofungin 50 mg/d; Group 2: Flu median 200 mg/day	Similar 6 m IFI occurrence [5.2% b (G1) vs 12.2% (G2)]. Reduced risk of IA in LT receiving caspofungin. Similar overall mortality
Chen et al[34], 2016	Single center study. 2005-2014. Effectiveness of targeted prophylaxis (n = 402)	Group 1: Anidulafungin 100 mg/day or micafungin 100 mg/day; Group 2: No prophylaxis	High risk patients MELD > 20; Similar IFI occurrence lower cumulative mortality in group 1 (P = 0.001)
Giannella et al[35], 2016	Retrospective, single center. 2010-2014. Evaluation of RF for a targeted prophylaxis (n = 303)	Group 1: No RF. No prophylaxis; Group 2: 1RF IC, Flu; Group3: High risk, anti mould agent	Antifungal prophylaxis administered to 45.9% patients. Cumulative IFI prevalence 6.3%. Flu independently associated with IFI development
Lavezzo et al[36], 2018	Single center study. 2011-2015. Effectiveness of targeted prophylaxis	Group 1 high risk: AmB; Group 2 low risk: No prophylaxis	Overall IFI prevalence 2.8%. 1 yr mortality higher in prophylaxis group (P = 0.001). 1 yr mortality higher in IFI patients (P < 0.001)
Jorgenson et al[37], 2019	Single center study. 2009-2016. Effectiveness of fixed dose prophylaxis (n = 189)	Group 1: Flu 400 mg/day for 14 d for high risk patients; Group 2: unsupervised antifungal protocols	Reduction in 1 yr IFI among high risk group (12.5% vs 26.6%). Similar 1 yr patient and graft survival
Kang et al[38], 2020	Multicenter, randomized, open label. Living donor LT. 2012-2015 (n = 144)	Group 1: Micafungin	Group 1 vs Group 2: 69 vs 75 pts. IFI occurrence in 3 wk: 1/69 vs 0/75. Micafungin was noninferior to Flu
		100 mg/d; Group 2: Flu 100-200 mg/day

AmB: Amphotericin-b; Flu: Fluconazole; Caspo: Caspofungin; AE: Adverse effects; Vori: Voriconazole; ppx: Prophylaxis; gp: Group; IA: Invasive aspergillosis; IC: Invasive candidiasis.