Risks and treatment strategies for de novo hepatitis B virus infection from anti‐HBc‐positive donors in pediatric living donor liver transplantation

The aim of this study was to analyze the incidence and risk factors of de novo HBV infection in pediatric patients receiving living donor liver transplants (LDLT) from HBcAb‐positive donors, and to explore its treatment strategies. The data of 101 pediatric recipients receiving LDLT in Tianjin First Central Hospital between September 2006 and December 2012 were retrospectively analyzed. The HBV markers were regularly tested before and after the surgery, including HBsAb, HBsAg, HBeAg, HBeAb, and HBcAb. The median follow‐up period was 25.6 months, during which eight cases (7.92%) were diagnosed with de novo HBV infection. Forty‐four (43.6%) of the children received HBcAb‐positive allografts. The rate of de novo HBV in the children that received HBcAb+ livers vs those received HBcAb? livers was 15.9% (7/44) vs 1.7% (1/57) (P=.037). The rates of de novo HBV in the children who received HBcAb‐positive allografts were significantly less than in those that received preventative therapy with HBIG and lamivudine treatment (2/31, 6.4%) vs those that did not (5/13, 38.5%) (P<.01). HBcAb‐positive liver donors are strongly associated with de novo HBV in HBsAg‐negative pediatric patients receiving LDLT. However, the incidence of de novo HBV infection is significantly less with the use of prophylactic treatment strategies.     

Long‐term follow‐up of de novo allergy in pediatric liver transplantation – 10 yr experience of a single center

We conducted a study to clarify the incidence, clinical course, and risk factors of de novo allergies after liver transplantation. Ninety‐three patients who had been followed longer than one yr and who had no previous allergy history were included. Forty‐two patients (45.2%) developed de novo allergy. Of them, food allergy developed in 35 (37.6%). Respiratory allergy was observed in three (3.2%), and a patient (1.1%) had drug allergy. Fifty‐two (55.9%) of the 93 patients developed eosinophilia. The median age of patients with de novo allergy was 15 months (IR 11.3–20 months). De novo allergy developed five months after liver transplantation (IR 2.3–9.5 months) and lasted for 16 months (IR 8–34.5 months). Younger age at liver transplantation displayed statistically significant differences in development of allergy between allergy and non‐allergy groups. Twenty‐nine (69.0%) patients improved from allergy during the follow‐up period. No patient with de novo gastrointestinal allergy progressed to any respiratory allergy such as asthma. Older age at transplantation, EBV non‐risk, and CMV non‐risk had statistical significance in allergy improvement. Younger age at transplant predisposes to the development of allergy, while improvement of allergy is achieved more in older age.     

De novo hepatitis B virus infection after pediatric liver transplantations with hepatitis B core antibody‐positive donors: A single‐center 20‐yr experience

DNHB is common in countries with high prevalence of hepatitis B, and therefore, contracting hepatitis B after LT with HBcAb⁺ grafts is a major concern. We studied DNHB in 247 children (aged <18 yr) who underwent LT from 1994 to 2013. Sixty‐six of 247 recipients received HBcAb⁺ donor grafts. The incidence of DNHB was 5.7% (14 of 247 children) and that in HBcAb⁺ donor grafts was 19.7% (13 of 66 children). The incidence of DNHB without LAM prophylaxis was 31.3% (nine of 29 children), while that with prophylaxis was 10.8% (four of 37 children). LAM prophylaxis negatively correlated with DNHB by Cox regression analysis (p = 0.028, odds ratio = 0.258). Among 13 DNHB patients with HBcAb⁺ donor grafts, eight recovered from DNHB and four showed the emergence of LAM resistance. There was no DNHB‐related graft failure. This study showed that HBcAb⁺ donor graft was associated with development of DNHB, and use of LAM prophylaxis decreased the incidence of DNHB with HBcAb⁺ graft.     

Long-term protection against hepatitis B in pediatric liver recipients can be achieved effectively with vaccination after transplantation

Liver recipients who have antibodies to hepatitis B core antigen (anti-HBc) or received an anti-HBc positive liver graft are at risk of acquiring de novo hepatitis B infection so a life long prophylaxis is required. A post-transplant vaccination against hepatitis B virus (HBV) can offer a better alternative than either hepatitis B hyperimmune globulin (HBIG) or lamivudine. This study investigated the course of anti-HBs titer after vaccination and analyzed the factors that influence the response. Between October 1999 and February 2003, 37 pediatric patients were given a post-transplant vaccination when an anti-HBc positive graft was used, the recipient was anti-HBc positive, or when anti-HBs titer was below 20 IU/L irrespective of the serological status. Thirty-three patients responded to the vaccine and did not require further HBIG injections at a mean follow up of 33.6 months. Fifteen patients were good responder and only needed a single set of vaccines, and 18 were poor responder needing additional boosters. Two patients developed de novo hepatitis B infection and two required additional HBIG injections. Preoperative severity of liver disease, serological status of HBV of recipient or donor, use of HBIG or pulse steroid therapy, type of vaccines, and dose or time interval between doses had no influence on response rate. Recipients with a high preoperative anti-HB titer, small graft-recipient weight ratio (GRWR), greater catch up growth, heavier body weight, lower tacrolimus level at the time of vaccination, and longer time interval between transplant or steroid medication and vaccination yielded good response. If well tailored, post-transplant vaccination can be effective and offer patients prophylaxis against de novo hepatitis B infection for a prolonged period of time.     

Clinical and histopathologic features of antibody‐mediated rejection among pediatric renal transplant recipients with preformed vs de novo donor‐specific antibodies

Preformed and de novo donor specific antibodies (pDSA and dnDSA) are risk factors for ABMR. This study compares the effects of pDSA vs dnDSA in pediatric kidney transplant recipients. Sixteen pediatric patients with biopsy‐proven ABMR were evaluated. Strong DSA (MFI >10 000) was recorded at transplant, rejection, and follow‐up. DSAs with the highest MFI were termed iDSAs. Allograft biopsies were scored according to Banff 2013 criteria. Seven of 16 (44%) patients had pDSA at transplant; 9 (56%) developed dnDSA. Patients with pDSA developed ABMR earlier (median = 63 vs 1344 days, P = .017), while patients with dnDSA were more likely to have strong Class II iDSA (100% vs 28%, P = .009). Viral infection or non‐adherence was more common in patients developing dnDSA (88.8% vs 28.6%, P < .01). Pathology in those with pDSAs demonstrated worse transplant glomerulitis (g score 1.57 ± 0.98 vs 0.56 ± 0.73, P = .031); however, those with dnDSAs exhibited higher C4d+ ABMR (P = .013). Patients developing dnDSAs showed ABMR later post‐transplant with predominance of HLA‐Class II iDSAs. Inadequate immunosuppression likely contributes to dnDSA formation. Patients with no DSA who have unprotocolized decreases in immunosuppression should be screened for dnDSA as it could lead to early intervention and potentially better outcomes.     

Antiviral treatment of chronic hepatitis B with lamivudine in pediatric renal transplantation

Renal transplantation in patients with chronic hepatitis B virus (HBV) infection is known to be associated with an increased risk for exacerbation of liver dysfunction. Lamivudine has been proven to be a potent inhibitor of hepatitis B virus replication in adults after kidney transplantation. Little is known about its efficacy and safety in pediatric renal transplant recipients. Three cases serve for the discussion to demonstrate the complexity of the clinical course and effective treatment of chronic hepatitis B in pediatric patients awaiting renal transplantation. Two patients on dialysis with a high HBV replication rate were treated with lamivudine before transplantation. After the viral load had decreased below the detection limit, they underwent transplantation successfully. Despite intensified immunosuppression to treat a rejection episode in one and a relapse of the nephrotic syndrome in the other patient, the viral load remained <2.5 pg/mL. Both patients developed a mutation in the YMDD motif of the HBV genome associated with an increase in the HBV replication rate >10,000 pg/mL without deterioration of the liver function. In a third patient with a chronic HBV infection with a low replication rate, lamivudine was started about nine months after kidney transplantation due to an increasing viral load after treatment of an acute rejection episode. Six months later, the HBV DNA was no longer detectable. The patient had no signs of liver dysfunction. Lamivudine in the treatment of chronic HBV infection in pediatric renal recipients seems to be safe and effective in preventing acute liver deterioration. Three clinical cases are discussed with regard to current options in monitoring and antiviral treatment of chronic HBV in pediatric renal transplant recipients.     

Hepatitis B immunoglobulin in combination with lamivudine for prevention of hepatitis B virus reactivation in children undergoing bone marrow transplantation

There is little information in literature about the use of hepatitis B immunoglobulin (HBIg) in recipients of bone marrow transplantation (BMT). Here, we report two children who received IV HBIg (Hepatect-CP) and lamivudine treatment during BMT course for either patient or donor hepatitis B virus (HBV) viremia. A four-year-old girl underwent a fully human leukocyte antigen-matched allogeneic BMT for thalassemia major from her mother positive for hepatitis B surface antigen (HBsAg). A 12-yr-old boy with chronic myeloid leukemia, positive for HBsAg and HBV-DNA received a fully HLA-matched allogeneic BMT from his sister in the first chronic phase of the disease. HBIg was successfully used in both cases to prevent HBV reactivation of the recipients. The results of our observations are encouraging and we suggest that HBIg in combination with lamivudine may be used in such cases especially in post-transplant early period to prevent HBV reactivation.     

Reduced immune response to hepatitis B vaccine in children with insulin dependent diabetes

Twenty-four patients with moderately controlled insulin dependent diabetes with a duration of diabetes ranging from 2 to 10 years as well as 17 control subjects were vaccinated against hepatitis B virus using Gen Hevac B vaccine. The vaccine was injected 0.5 mL intramuscularly into the deltoid region on three separate occasions at intervals of 1 month. If subjects were still negative for anti-hepatitis B surface antigen (HBs) or had inadequate antibody after the third injection, a fourth administration of vaccine was given 3 months later. The mean anti-HBs titer was 243.3 ± 97.2 mi.u./mL in control subjects and 39.8 ± 53.2 in diabetic patients (P < 0.001). In the control group optimal protection was obtained in 100% of subjects, whereas 11 diabetic patients (45.8%) had low anti-HBs titer (< 10 mi.u./mL). All of 11 diabetic patients showed adequate (> 10 mi.u./mL) anti-HBs titer after the fourth dose of vaccine. In diabetic patients the most striking feature was the reduced CD4/CD8 ratio which was significantly lower (P < 0.001) than that of the control group. We conclude that diabetic children have an impaired immune response to hepatitis B vaccine. It is suggested that diabetic children should be vaccinated against hepatitis B virus with four injections instead of three.     

Analysis of rabbit anti‐thymocyte globulin vs basiliximab induction in pediatric liver transplant recipients

Literature is limited comparing induction immunosuppression in pediatric liver transplant (LTx) recipients. This is a single‐center, retrospective cohort study of primary pediatric liver transplants at our center between 2005 and 2016 who received either basiliximab (BSX) or rabbit anti‐thymocyte globulin (rATG) induction. Maintenance immunosuppression consisted of tacrolimus ± a corticosteroid taper. Exclusions included receipt of an ABO‐incompatible graft, retransplantation, and multi‐organ transplantation. Primary outcomes were incidence of treated biopsy‐proven acute rejection (tBPAR) and PTLD within the first year and infections within 90 days of LTx. Secondary outcomes included graft and patient survival, time to first tBPAR, and incidence of steroid‐resistant rejection (SRR) within the first year post‐LTx. A total of 136 patients were included in the final analysis of which 57 patients (42%) received BSX induction. Patients who received rATG induction with or without a 2‐week corticosteroid taper experienced significantly more tBPAR compared to those who received BSX induction with a 6‐month corticosteroid taper (55.7% vs 33.3%, P = .01). There were no differences in the incidence of PTLD, infections, SRR, graft or patient survival, or time to first tBPAR between the two groups . Induction with rATG either with or without a short corticosteroid taper was associated with significantly more tBPAR in primary pediatric LTx recipients when compared to BSX induction with a prolonged corticosteroid taper in the setting of maintenance immunosuppression with tacrolimus.     

Long‐term outcomes of de novo autoimmune hepatitis in pediatric liver transplant recipients

The long‐term course and outcome of DAIH is unknown. A retrospective multicenter study assessing associations and long‐term consequences of DAIH developing in a transplanted allograft is presented. Children with DAIH were followed from diagnosis until death, re‐LT, or transfer of care and for a minimum of 1 year. A total of 31 patients of 1833 (1.7%) LT were identified; 29 followed for a median of 7.1 years (range, 1.6‐15); 52% had no rejection preceding diagnosis of DAIH. Transaminases fell following treatment with steroids and antimetabolites (ALT 108 vs 39 U/L (P=.002); AST 112 vs 52 U/L (P=.003); GGT 72 vs 36 U/L (P=.03), but this was not universally sustained. Transaminases >2X ULN observed in 38% of patients at last follow‐up; commonly GGT, attributed to bile duct injury and ductopenia. Portal hypertension (PHT) was seen in four patients and associated with severe fibrosis and cirrhosis. Re‐LT occurred in two patients for chronic rejection (CR) and uncontrolled PHT with gastrointestinal bleeding, respectively. No deaths from DAIH were reported. DAIH is an uncommon complication following pediatric LT requiring prolonged and augmented immunosuppression. It is associated with continued allograft dysfunction and may lead to bile duct injury, CR, and PHT necessitating re‐LT.     

De novo hepatocellular carcinoma post‐multivisceral transplantation in a child

De novo hepatocellular carcinoma (HCC) post‐transplantation in patients without viral hepatitis is extremely rare, with only three reported adult cases in the English literature. Here, we present a case of de novo HCC that developed in a 7‐year‐old female, who at 8 months of age received a liver, small bowel, spleen, and pancreas transplantation 6.5 years ago for gastroschisis and total parenteral nutrition (TPN)‐related cirrhosis. The post‐transplant course was complicated by Epstein‐Barr virus (EBV) infection, post‐transplant lymphoproliferative disease, and subsequent development of multifocal EBV‐associated post‐transplant smooth muscle tumors (EBV‐PTSMT) in the small bowel 1 year and 10 months after transplantation, respectively. This was managed by reducing immunosuppression with rituximab and EBV‐specific cytotoxic T‐cell therapy. She was noted to have a new lesion in her transplanted liver graft 6.5 years post‐transplantation that was diagnosed as HCC. The HCC was resected, and the patient remained clinically stable for 7 months. At that time, recurrence of the HCC was discovered on MRI. She passed away 6 months after. To the best of our knowledge, this is the first reported occurrence of de novo HCC post‐transplantation in the pediatric population that is unrelated to viral hepatitis in either recipient or donor.     

不同孕周早产儿接种乙肝疫苗后的免疫反应性

目的 探讨不同孕周早产儿生后短时间内接种乙肝疫苗的免疫反应性.方法 将孕周为30～36周的早产儿分为两组:组Ⅰ 30～33周,组Ⅱ34～36周;组Ⅲ为≥38周的健康足月儿.组Ⅰ、组Ⅱ于生后1周内接种基因乙肝疫苗5 μg(0.5 ml),第2、第3次于生后1、6月龄时接种;组Ⅲ按(0、1、6月,5 μg)方案常规接种,三组均于第3次乙肝疫苗接种后4个月左右查抗-HBs滴度.若母亲是乙肝病毒携带者,出生12 h内注射抗乙肝免疫球蛋白(HBIg)0.5 ml.结果 完成随访者组Ⅰ 28例,组Ⅱ32例,组Ⅲ39例.抗-HBs滴度:组Ⅰ为(570±388)mIU/ml,组Ⅱ(669±401)mIU/ml,组Ⅲ(693±286)mIU/ml,三组比较,差异无统计学意义(H=1.20,P＞0.05);抗HBs强应答所占百分比:组Ⅰ 22/28例(78.6%),组Ⅱ28/32例(87.5%),组Ⅲ37/39例(94.9%),三组比较差异有统计学意(x2=198,P＜0.01).结论 早产儿出生不久即接种乙肝疫苗,其抗体水平产生较好,早产儿强应答百分比低于足月儿,以30～33周早产儿更为明显.     

Early post‐operative intravenous tacrolimus in pediatric liver transplant recipients is not superior to oral tacrolimus

We aimed to compare the early results of i.v. with p.o. TAC as a primary immunosuppressant in pediatric patients undergoing LT. This retrospective study enrolled 75 children who underwent LT and received TAC‐steroid regimens as a primary immunosuppressant between September 2011 and October 2015 at our institution. Thirty‐five recipients received TAC i.v. and 40 received TAC p.o. Early results were evaluated and compared, including ACR, EBV, or CMV infection; renal adverse effects; and hospital stay. Comparisons of 90‐day post‐transplant results showed that the rates of overall viral (74% vs 40% P < 0.002), EBV (46% vs 17.5% P < 0.008), and CMV (51% vs 30% P = 0.05) infections were significantly higher in the i.v. than in the p.o. group. Neither regimen has any adverse effects on renal function. There were no between‐group differences in ACR incidence and severity, serum creatinine concentration, and hospital stay. Patient and graft survival rates at 3 months and 1 year did not differ significantly between the two groups. Compared with p.o. treatment, i.v. administration of high TAC concentration did not have beneficial post‐transplant effects on ACR incidence and severity, while increasing the incidence of viral infections in pediatric LT.     

Clinical consequences of human herpesvirus‐6 DNAemia in peripheral blood in pediatric liver transplant recipients

The significance of HHV6 DNAemia after solid organ transplantation has not been fully determined. Our objectives were to determine the prevalence of HHV6 DNAemia in pediatric liver transplant recipients and to describe the associated clinical characteristics and outcomes. This was a retrospective case–control study. Eligible liver transplant patients aged ≤ 18 yr with HHV6 DNAemia were matched with two subjects without HHV6 DNAemia. Matching was by age ± 6 months. Among 154 subjects, 25 patients (16%) had HHV6 DNAemia detected by PCR in whole blood or plasma (M:F ratio = 0.9:1). While 28% of subjects with DNAemia (7/25) had symptoms consistent with HHV6 infection, active infection was detected in only four subjects (2.6% of liver transplant patients). The major symptoms/signs were fever, vomiting, lethargy, splenomegaly, bone marrow suppression, and elevated transaminases. The prevalence of DNAemia due to other herpesviruses in cases vs. controls was EBV 56% vs. 60%, CMV 12% vs. 12%, HHV7 20% vs. 12%; p value is not significant for all pairwise comparisons. HHV6 DNAemia in pediatric liver transplant patients is not an uncommon entity. While the clinical relevance is still not entirely established, active HHV6 infection and attributable symptoms are relatively rare.     

Centrilobular necrosis as a manifestation of venous outflow block in pediatric malnourished liver transplant recipients – case reports

Gibelli NEM, Tannuri ACA, Andrade WC, Ricardi LRS, Tannuri U. Centrilobular necrosis as a manifestation of venous outflow block in pediatric malnourished liver transplant recipients – case reports. Abstract: CLN is a frequent histological finding in biopsies after pediatric: LT, and its pathogenesis has not yet been fully clarified and has different causes. Among the vascular causes, VOB is sometimes difficult to diagnose, especially when technical variants such as split‐liver, reduced‐liver, or living‐related LT are utilized. Three liver‐transplanted malnourished children (ages 12, 20, and 28 months) developed altered LFTs and post‐operative ascites with right pleural effusion (two cases) and jaundice (one case). Doppler ultrasound examinations were normal and liver biopsies showed CLN interpreted as severe ACR. There were no responses to the medical treatment. Additional investigation with CT angiography suggested obstructed hepatic vein drainage, which was confirmed by interventional radiology and angioplasty of the anastomosis between the hepatic vein and the inferior vena cava, with clinical and histological resolution. It is concluded that in malnourished children undergoing LT with technical variations, in which the occurrence of severe ACR is usually less common because of the severity of the patient condition, the finding of CLN should raise the possibility of VOB, so that excessive immunosuppression and its consequences can be avoided.     

Outcome of duct‐to‐duct vs. Roux‐en‐Y hepaticojejunostomy biliary anastomoses in below 15‐kg pediatric liver transplant recipients

The best type of biliary anastomosis to use in lower weight pediatric liver transplant recipients is debatable. In this study, we share a single center's experience comparing the rate of anastomotic biliary complications based on the type of biliary anastomosis performed in this population of patients. A retrospective review of pediatric liver transplants for recipients weighing <15 kg from 11/2003 till 12/2011 was performed. Patients were grouped based on the type of biliary anastomosis into two groups: duct‐to‐duct (d‐d) and Roux‐en‐Y hepaticojejunostomy (h‐j) anastomoses. A total of 24 patients (12 males, 12 females) with a mean age of 26 ± 20 months and a mean weight of 9.27 ± 2.63 kg (range = 5.3–13.9 kg) were studied. All anastomotic complications occurred in patients who received left lateral segments. No statistical differences were found in the post‐operative biliary (p = 0.86) or vascular (p = 0.99) complications between the two groups. Acknowledging the limited sample size, our data suggest that duct‐to‐duct anastomosis can be performed safely in pediatric liver transplantation recipients weighing below 15 kg.