Intravenous immunoglobulins in liver transplant patients: Perspectives of clinical immune modulation

Table 1 Clinical data of prognostic relevant immune modulation by hepatitis B hyperimmunoglobulin after liver transplantation

Ref.	No. of patients receiving HBIg	Efficacy of HBIg on immunology/survival
Farges et al[80]	n = 116	Significant reduction (P < 0.05) of acute and chronic rejection rate (1.7%) compared to other indications like PBC (6.1%), PSC (13%), AIC (17%), and HCV (9.2%), without increased risk of bacterial infection; significantly lower risk (P < 0.05) of death or retransplantation from rejection or either sepsis or de novo malignancy (3.5%) compared to patients with alcoholic cirrhosis (19%)
Couto et al[81]	n = 12	Significantly less acute rejection episodes (0.3 ± 0.5) as compared to HBsAg-positive (0.9 ± 0.7; P = 0.02) and HBsAg-naïve (0.7 ± 0.7; P = 0.03) liver transplant patients without HBIg therapy
Kwekkeboom et al[82]	n = 40	Sigificantly lower rate of acute rejection (12%) as compared to patients without viral hepatitis (34%; P = 0.012); only HBIg treatment (HR = 0.39, 95%CI: 0.16-0.99, P = 0.047) and year of LT (HR = 0.87, 95%CI: 0.78-0.98, P = 0.017) were identified as independent predictors of acute rejection
Wang et al[83]	n = 1000	Reduction of HBV recurrence rate and of viral mutants; significantly improved 1-yr (P = 0.03) and 3-yr survival (P = 0.005) as compared to an antiviral prophylaxis without HBIg

HBIg: Hepatitis B hyperimmunoglobulin; HBV: Hepatitis B virus; HCV: Hepatitis C virus; LT: Liver transplantation; PBC: Primary biliary cirrhosis; PSC: Primary sclerosing cirrhosis; AIC: Autoimmune cirrhosis; HBsAg: Hepatitis B surface antigen.

Table 2 Clinical data of prognostic relevant immune modulation by hepatitis B hyperimmunoglobulin in recipients of hepatitis B virus-positive liver allografts

Ref.	HBV characteristics donor/recipient	Antiviral prophylaxis	Impact of HBIg on outcome
Brock et al[94]	HBc+/HBsAg- (n = 958)	HBIg alone: n = 61	70% reduction in risk of mortality by HBIg prophylaxis;
		HBIg + Lam: n = 66	(HR = 0.29, 95%CI: 0.10-0.86, P = 0.026)
		Lam alone: n = 116
		None: n = 509
		Missing data: n = 206
Li et al[112]	HBsAg+/ HBsAg- (n = 63)	With HBIg: n = 17	HBIg independently associated with superior
	HBsAg+/HBsAg+ (n = 15)	Without HBIg: n = 61	posttransplant graft survival;
		With Lam: n = 14	(HR = 0.23, 95%CI: 0.06-0.81) and patient survival
		Without Lam: n = 64	(HR = 0.16, 95%CI: 0.04-0.759)

HBV: Hepatitis B virus; HBIg: Hepatitis B hyperimmunoglobulin; HBc+: Hepatitis B core +; HBsAg: Hepatitis B surface antigen.

Table 3 Clinical data of prognostic relevant immune modulation by cytomegalovirus immune globulin after liver transplantation

Ref.	No. of patients receiving CMVIg	Efficacy of CMVIg on immunology/survival
Farges et al[80]	n = 19	Significant reduction of acute rejection rate (19%) compared to recipients without CMVIg (48%; P = 0.01); no impact of on incidence of chronic rejection and bacterial infections
Falagas et al[121]	n = 90	Improved 1-yr survival (86% vs 72%; P = 0.029) and a clear trend towards improved long-term survival (68% vs 54%; P = 0.055). CMVIg as independent predictor of beneficial outcome at one year post-LT (P = 0.042)
Bucuvalas et al[124]	n = 336	Lower rate of acute rejection at 3-mo (31% vs 40%; P = 0.02); (CMV)Ig treatment as independent predictor for absence of acute rejection (HR = 0.73; P = 0.0019); significantly increased death-free allograft survival (HR = 0.57; P = 0.014) by (CMV)Ig
Fisher et al[125]	n = 2805	Significantly lower risk of graft loss and recipients' death (with or without additional antiviral agents; P < 0.001) at 7 yr post-LT; significantly higher 7-yr-survival rate after CMVIg monoprophylaxis (72%) vs no prophylaxis (67%; P = 0.02)

CMVIg: Cytomegalovirus immune globulin; LT: Liver transplantation.

Table 4 Clinical data of immune modulation by intravenous immunoglobulins in liver transplant recipients with positive lymphocytotoxic crossmatch

Ref.	Transplant procedure	No. of patients receiving IVIg (pre-LT/post-LT)	Additional immune modulation	Efficacy of IVIg on outcome
Watson et al[150]	LT	n = 1; post-LT, after detection of AMR	Plasmapheresis, rituximab	Intermittent decrease of Bili, liver enzymes and DSAs'; no survival
Dar et al[151]	SLKT	n = 6; pre- and post-LT desensitization	-	Survival rate 83.3%
Kozlowski et al[142]	LT	n = 3; post-LT, after detection of AMR	Plasmapheresis, rituximab	Transient decrease of Bili, yGT and DSAs' in 2 patients; survival rate 33.3%
Koch et al[153]	SLKT	n = 1; post-LT, after liver function deterioration and detection of DSAs'	Splenectomy, plasmapheresis, bortezomid	Improvement of liver/kidney function; decrease of DSAs'; survived
Shindoh et al[154]	LDLT	n = 1; post-LT, after decrease of platelet count and increase of attacking IgG	-	Recovery of platelet count; decrease of attacking IgG; survived
Leonard et al[137]	LT	n = 2; post-LT, after liver function deterioration	-	Recovery of allograft function; survival rate 100%
Hong et al[155]	LDLT	n = 1; post-LT, desensitization	-	Survived

IVIg: Intravenous immunoglobulins; LT: Liver transplantation (full size deceased); SLKT: Simultaneous liver-kidney transplantation; LDLT: Living donor liver transplantation; AMR: Antibody-mediated rejection; DSAs: Donor-specific antibodies.

Table 5 Clinical data of immune modulation by intravenous immunoglobulins in ABO-incompatible liver transplant recipients

Ref.	Transplant	No. of patients receiving	Additional immune modulation	Efficacy of IVIg on immunology/survival
	procedure	IVIg (pre-LT/post-LT)
Morioka et al[167]	LDLT	n = 2; post-LDLT; treatment of AMR	Plasmapheresis	Normalization of liver function; survived
Urbani et al[170]	LT	n = 1; post-LT; treatment of AMR	Plasmapheresis	Normalization of liver function; survived
Ikegami et al[168]	LDLT	n = 1; post-LDLT; treatment of AMR	Rituximab, plasma exchange, splenectomy	Normalization of liver function; survived
Testa et al[169]	LDLT	n = 5; pre-LDLT	Plasmapheresis, splenectomy	Patient and graft survival 80% at mean of 43 mo post-LDLT
Urbani et al[172]	LT	n = 8; pre- and post-LT	Plasma exchange	Patient and graft survival 87.5% at 18 mo; no case of acute or chronic rejection, no ITBL
Ikegami et al[161]	LDLT	n = 4; post-LDLT	Rituximab, plasma exchange, splenectomy	Survival rate 100% (28, 8, 6, 5 mo post-LDLT)
Takeda et al[173]	LDLT	n = 3; post-LDLT; treatment of AMR	Plasma exchange	Normalization liver function; survived
Mendes et al[174]	LT	n = 10; pre- and post-LT	Rituximab, plasmapheresis	Survival rate 50%; death mainly related to MOF and sepsis
Kim et al[175]	LDLT	n = 14; post-LDLT	Rituximab, plasma exchange	Survival 100%; no case of acute or chronic rejection
Lee et al[176]	LDLT	n = 15; post-LT	Rituximab, plasma exchange	Survival 100%; no case of bacterial or fungal infection; 3 cases of biliary strictures
Shen et al[177]	LT	n = 35; pre- and post-LT	Rituximab	Survival rate 83.1% at 3-yr; one case of acute celluar rejection; two cases of AMR

IVIg: Intravenous immunoglobulins; LT: Liver transplantation (full size deceased); AMR: Antibody-mediated rejection; LDLT: Living donor liver transplantation; MOF: Multi organ failure; ITBL: Ischemic-type biliary lesions.