| Objective: To analyze the risk factors and evaluate the efficacy of HBV vaccine prophylactic strategies for de novo HBV infection in pediatric liver transplantation recipients receiving HBcAb positive grafts.Method: 1.150 cases of pediatric liver transplantation that were carried out by Tianjin First Central Hospital between Aug 2012 and Nov 2014 were retrospectively analyzed.According to serum HBcAb testing result of donors,the patients were divided into HBcAb(+)group and HBcAb(-)group.Comparative analysis was made between the two groups on the incidence of de novo HBV infection and clinical data.According to the incidence of de novo HBV infection after pediatric liver transplantation,the patients were divided into de novo HBV group and non-de novo HBV group.Gender of the donors,serum HBcAb test results,HBV cccDNA test results of the donor liver,operation time of the pediatric liver transplantation,intraoperative blood loss,intraoperative erythrocyte infusion volume,intraoperative plasma infusion volume,total intraoperative infusion volume,donor age,donor weight,and graft weight were retrospectively analyzed.2.A prospective study was carried out at Tianjin first central hospital between Sep 2016 and Sep 2018.139 patients receiving HBcAb positive grafts were enrolled,all of whom received an enhanced hepatitis B vaccine therapy to prevent de novo hepatitis B infections.Clinical data of donors and recipients were recorded.According to the changes of HBs Ab within 3 months after the operation,they were divided into Group A: HBs Ab titration>1000IU/L,Group B: HBs Ab titration 200-1000IU/L and Group C: HBs Ab titration<200IU/L.Donor and recipient features,operative information along with graft and recipient outcomes were compared between recipients with or without de novo HBV infection.Univariate and multivariate analysis were applied to identify the risk factors of that affect the efficacy of the active immunization treatment of hepatitis B vaccine.3.According to the number of hepatitis B vaccine before surgery,the pateints were divided into strong response group(≤ 3),medium response group(4-6),and weak response group(> 6).Before vaccine,1 week after and 2 weeks after the vaccine,the proportion of lymphocyte in peripheral blood was detected by Flow cytometry and the difference of perforin and granzyme B was detected by RT-PCR.The difference of IL-2 and IFN-γ was determined by ELISA.The expression of TLR3,TLR9 and RIG-1 protein and mRNA in NK cells was detected by Western blot and RT-PCR.Results: 1.125 cases were enrolled,including 47 cases in HBcAb(+)group and 78 cases in HBcAb(-)group,the number of de novo HBV infection of two groups were 8 cases and 1 case respectively.The difference was statistically significant(P < 0.05),and the remaining clinical data was not statistically significant.From all donor liver,11 cases of HBV cccDNA positive were detected(testing rate: 8.8 %).Among them,10 cases came from HBcAb(+)group(21.3 %),but only 1 case came from HBcAb(-)group(1.3 %),and the difference was statistically significant(P < 0.05).4 of 11 cases who received HBV cccDNA(+)donor liver suffered de novo HBV infection after liver transplantation(infection rate: 36.4 %),and among other 114 cases who received HBV cccDNA(-)donor liver,5 cases suffered de novo HBV infection(infection rate: 4.4 %),with the difference was statistically significant(P < 0.05).Compared with the de novo HBV group and non-de novo HBV group,the serum HBcAb test results of donors and the HBV cccDNA test results of donor liver tissues were statistically significant(P < 0.05).The number of donor serum HBcAb(+)and donor liver tissue HBV cccDNA(+)were higher in de novo HBV group than those of the non-de novo HBV group(P < 0.001).And the donor serum HBcAb(+)was associated with the donor liver tissue HBV cccDNA(+).2.The mean follow-up time was 23.5 ± 15.7 months,and there were 5 cases(3.6 %)with de novo HBV infection.The average time of de novo HBV infection after liver transplantation was 11.6 months(6-18 months).Recipients with de novo HBV infection showed equal graft and recipient outcome compared with the recipients without de novo HBV infection during the follow-up period.By multiple logistic regression analysis,HBs Ab titer<1000 IU/L before operation,HBV-DNA> 1000 copies of graft,the decline rate of HBs Ab within 3 months after operation and the plasma dosage> 400 ml were the main factor affecting outcomes of hepatitis B vaccine,and HBs Ab titer within 3 months after operation was related to the plasma dosage.3.After 1 week with the hepatitis B vaccine,the ratio of NK cells in peripheral blood and the ability of NK cells to secrete perforin and granzyme B,the contents of IL-2 and IFN-γ in serum,the expression of TLR3,TLR9 and RIG-I protein and mRNA in NK cells were significantly higher in the strong reaction group than those in the weak reaction group and the medium reaction group(P < 0.05).After 2 weeks with the hepatitis B vaccine,compared with the medium and strong response groups,the ratio of NK cells in peripheral blood and the ability of NK cells to secrete perforin and granzyme B,the content of IL-2 and IFN-γ in serum,the expression of TLR3,TLR9 and RIG-I protein and mRNA in NK cells were still significantly lower in the weak response group(P < 0.05).Conclusion: 1.Donor serum HBcAb(+)is a critical risk factor for de novo HBV infection after liver transplantation in children,which is related to HBV cccDNA(+)of donor liver.2.Active immunotherapy with hepatitis B vaccine can effectively prevent de novo HBV infection after liver transplantation in children with HBcAb positive donors.HBs Ab titer >1000 IU/L before operation is the key factor to reduce the incidence of de novo HBV infection after liver transplantation.3.The factors influencing the response intensity of hepatitis B vaccine in children are closely related to the proportion and function of NK cells,and the mechanism may be TLR3,TLR9 and RIG-I related pattern recognition receptor signaling pathway. |
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