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.     

Management of pediatric hepatocellular carcinoma: A multimodal approach

HCC is rare in the pediatric population, but is the second most common liver malignancy in children. Survival rates for primary unresectable HCC have been dismal. The objective of this study was to describe our experience with a multimodal approach for the management of unresectable HCC in two adolescent patients and to review the literature. Both patients are currently alive with no recurrence at 51 and 29 months post‐transplant. Multimodality treatment involving chemotherapy with doxorubicin, cisplatin, and sorafenib; TACE; timely liver transplantation; and post‐transplant therapy with sorafenib and mTOR inhibitors may help improve outcomes and prolong survival in pediatric patients with unresectable HCC.     

Hepatitis C viral recurrence in a pediatric patient following liver transplantation

Hepatitis C virus (HCV) infections are known to have a more benign course in children than in adults. Although the natural history of HCV recurrence after liver transplantation has been well studied in adult patients, much less is known about HCV recurrence after liver transplantation in pediatric patients. Herein, we report a case of a pediatric patient with HCV presumably acquired through vertical transmission. She underwent liver transplantation at 14 yr of age. The first three yr after liver transplantation were uneventful. However, in the past 12 months she has been hospitalized twice after developing ascites, hematemesis and esophagogastroduodenoscopy (EGD)-documented esophageal varices. Post-transplant biopsy has demonstrated chronic inflammation complicated with active hepatitis C and stage 2-3 scarring. This case report demonstrates the need for further epidemiologic studies to study the natural history of the rate of HCV recurrence after liver transplantation in the pediatric population.     

Management of tacrolimus‐associated food allergy after liver transplantation

Increasingly, food allergy associated with tacrolimus after pediatric living‐donor liver transplantation (LT) has been reported. Tacrolimus prevents the activation of T cells by blocking calcineurin, thus producing an immunosuppressive effect, but tacrolimus induces an imbalance in T‐helper type 1 (Th1) and Th2 cells in the food allergy process. This report describes a case of tacrolimus‐associated food allergy after pediatric living‐donor LT. The patient was a 7‐year‐old Japanese girl who had undergone living‐donor LT at 12 months of age, and whom we first saw in the clinic at age 18 months. She received immunosuppressive therapy by tacrolimus after transplantation. Atopic dermatitis developed in post‐transplant month 18. Stridor, facial edema, lip swelling, and skin erythema after consuming tempura udon containing wheat occurred in post‐transplant month 39, and she was subsequently diagnosed with anaphylactic shock. Eosinophilic leukocyte and serum immunoglobulin (Ig)E increased, and specific IgE was positive for some food allergens. Pharmacotherapy was therefore changed from tacrolimus to cyclosporine A, after which eosinophilic leukocyte and serum IgE decreased and atopic dermatitis improved.     

Outcomes in pediatric hepatitis C transplant recipients: Analysis of the UNOS database

HCV may lead to the development of ESLD in late childhood and, consequently, contributes to the need for liver transplantation. The aim of this study was to examine post‐transplant outcomes in HCV‐positive pediatric patients with ESLD from any cause and to determine the impact of the PELD scoring system, introduced in February 2002, on post‐transplant patient and graft survival. A retrospective analysis of the UNOS database from 1994 to 2010 was performed to assess graft and patient survival in pediatric HCV‐seropositive liver transplant recipients. Graft survival and patient survival comparing subjects in the pre‐PELD era and post‐PELD era were analyzed using Kaplan–Meier statistics. Factors associated with survival were identified using Cox regression analysis. Of 120 pediatric HCV transplant recipients, 80 were transplanted in the pre‐PELD era and 40 were transplanted post‐PELD. Median serum total bilirubin, INR, and creatinine were 4.8 mg/dL, 1.6, and 0.7 mg/dL in the pre‐PELD era vs. 5.5 mg/dL, 1.7, and 0.6 mg/mL, respectively, in the post‐PELD era (p NS). One‐yr graft survival in the pre‐PELD vs. post‐PELD era was 65.0% and 89.7%, respectively (p < 0.01); corresponding three‐yr graft survival was 57.3% vs. 76.2% (p = 0.04). One‐yr patient survival in the pre‐PELD vs. post‐PELD era was 79.0% and 97.5%, respectively (p < 0.01); corresponding three‐yr survival was 79.0% vs. 89.4% (p = 0.17). Twenty‐eight patients (23.3%) were retransplanted: 24 (30%) in the pre‐PELD era (median time to retransplant 272 days) and four (10%) in the post‐PELD era (median time to retransplant 586 days). Early follow‐up demonstrates a trend toward improved pediatric HCV liver transplant graft and patient survival in the post‐PELD era. Superior outcomes may be attributed to pretransplant factors, improved surgical technique and better treatment options for HCV infection.     

Successful lung transplant in a child with cystic fibrosis and persistent Blastobotrys rhaffinosifermentans infection

Fungal respiratory infections in patients with CF are a significant concern both pre‐ and post‐lung transplantation (LTx). Fungal infection is associated with increased mortality post‐LTx, and in the past decade, the prevalence of fungal colonization in Canadian pediatric patients with CF has increased. The emergence of novel fungal pathogens is particularly challenging to the transplant community, as little is known regarding their virulence and optimal management. We present a case of a successful double‐lung transplant in a pediatric patient with CF who was infected pretransplantation with a novel yeast, Blastobotrys rhaffinosifermentans. This patient was treated successfully with aggressive antifungal therapy post‐transplantation, followed by extended fungal prophylaxis. The significance of fungal colonization and infection in children with CF pre‐ and post‐LTx is reviewed.     

Hepatitis C in children: a quaternary referral center perspective

INTRODUCTION: Chronic hepatitis C virus (HCV) infection affects 0.3% of children in the United States, and the general impression is that it has a benign course in childhood. We analyzed a pediatric population with chronic HCV in a quaternary referral center. MATERIAL AND METHODS: This is a retrospective clinical review comprising all patients with chronic HCV referred to the Pediatric Liver/Liver Transplant Program between January 1999 and December 2004. RESULTS: Ninety-one patients (52% female; mean age, 9 years) were assessed. Eight-three percent of the patients were genotype 1. Twenty-one patients received/are receiving interferon and ribavirin for chronic HCV (treatment indications--advanced disease, 9; clinical trial, 6; genotype 2, 2; social, 2; prerenal transplant, 1). Eight (53%) of 15 patients, who have completed therapy and follow-up, achieved sustained viral response. Seven of 91 patients had cirrhosis at presentation (mean age, 11.7 years). Four underwent liver transplantation, all experienced HCV recurrence, 2 died, 1 was retransplanted, and 1 has compensated cirrhosis. CONCLUSION: Although, in general, HCV in children has a slow progression, there are cases with an accelerated course and early development of cirrhosis requiring liver transplant. Hepatitis C virus recurs universally after transplant, and its prognosis is usually poor; therefore, the most promising long-term approach is to clear this infection before transplantation.     

An autoimmune disease refractory to immunosuppressive regimens: Celiac disease diagnosed long after liver transplantation

CD is defined as T‐lymphocyte‐mediated gluten sensitivity. Although CD is known to affect the small intestine, it is nonetheless a multisystem disorder. Liver involvement in CD may vary from isolated hypertransaminasemia to cirrhosis. Because CD is an inappropriate immune response to gluten proteins, strict gluten‐free diet is the principal therapy, along with management of liver dysfunction. In patients who fail to respond to a gluten‐free diet, immunosuppressive drugs may improve intestinal inflammatory activity in untreated CD. The present case report is of a 25‐yr‐old woman with diarrhea lasting several weeks. The patient had received a liver transplant 13 yr earlier, and presented with cryptogenic cirrhosis diagnosed as CD. This appears to be the first case of its kind in which a pediatric long‐term liver transplant patient presents with diarrhea eventually diagnosed as CD whose diet included gluten, and who was treated by an immunosuppressive drug regimen. Because of the normalization of CD‐related antibodies in the post‐transplantation period without gluten restriction, CD should be part of a list of diagnostic possibilities in liver transplant patients presenting with diarrhea of unknown etiology.     

Safety of allogeneic hematopoietic stem cell transplantation in beta‐thalassemia patients with chronic hepatitis C infections treated at a pediatric center

The outcome of allogeneic HCT in patients previously infected with HCV is a widely debated topic and rarely reported in the pediatric and young adult age group given the small population of affected patients. New medications directly targeting HCV have induced virologic cures for over 90% of patients, and their use in the pretransplant setting may improve outcomes for patients infected with HCV. We describe two patients with transfusion‐dependent beta‐thalassemia major who underwent matched sibling donor bone marrow transplantation, one with a myeloablative regimen and one with a reduced‐intensity conditioning regimen. Allogeneic HCT appears feasible in patients with HCV infection that clear viremia prior to conditioning therapy and with a reduced‐intensity conditioning regimen. Further investigation is warranted to better define transplant risks in this population.     

Varicella infection following vaccination in a pediatric kidney transplant recipient

Live viral vaccines have historically been avoided in children after solid organ transplantation. Multiple reports of safety and immunogenicity, largely in the pediatric liver transplant population, have led to a reconsideration of this recommendation. Here, we report the case of a 4‐year‐old boy who inadvertently received the live attenuated MMR‐varicella vaccine (MMRV) at a routine well‐child visit 16 months after receiving a living donor kidney transplant. This was not known until after he was admitted with rash and documented disseminated varicella infection 5 weeks later. He was treated with intravenous acyclovir followed by oral therapy and recovered fully. This case and its discussion illustrate what is still unknown about the risk‐to‐benefit ratio of live viral vaccination in any individual transplant recipient. Criteria to determine which patients should receive these vaccines should be evaluated before their use after transplant becomes routine, and all recipients and their families should be counseled to have a low threshold to seek medical care for any febrile illness or rash after live viral vaccination.     

Imaging in pediatric renal transplantation

Renal transplantation is the therapy of choice in children with ESKD. Radiological investigations are required in both pre‐ and post‐transplant assessment, although there is paucity of both consensus‐based statements and evidence‐based imaging guidelines in pediatric renal transplantation. The phases of pediatric ESKD management that require imaging are pretransplantation recipient assessment and post‐transplantation surveillance for detection of potential complications. We present suggestions for imaging algorithms for both pre‐ and post‐transplant assessment in pediatric renal transplant recipients.     

Pretransplantation combined therapy with plasmapheresis and rituximab in a second living-related kidney transplant pediatric recipient with a very high risk for focal segmental glomerulosclerosis recurrence

Chikamoto H, Hattori M, Kuroda N, Kajiho Y, Matsumura H, Fujii H, Ishizuka K, Hisano M, Akioka Y, Nozu K, Kaito H, Shimizu M. Pretransplantation combined therapy with plasmapheresis and rituximab in a second living‐related kidney transplant pediatric recipient with a very high risk for focal segmental glomerulosclerosis recurrence.
Pediatr Transplantation 2011. © 2011 John Wiley & Sons A/S. Abstract: Prophylactic PP can provide some protection against post‐transplantation recurrences of FSGS, but it cannot prevent recurrences in all cases. Therefore, new preventive therapies are needed. We report on a 7.9‐yr‐old girl treated with pretransplantation prophylactic combined therapy consisting of four sessions of PP and one dose of rituximab before a second living‐related KTX. The patient had a very high risk of post‐transplantation FSGS recurrence because this had occurred after the first KTX. During the 36 months since the second transplantation, she has had no evidence of proteinuria or significant infectious complications. Although our experience is too preliminary to draw any generalizable conclusions, pretransplantation combined therapy with PP and rituximab might be a possible option for the prevention of FSGS recurrence in very high‐risk recipients undergoing living‐donor KTXs.     

Hepatocellular carcinoma in a 10‐month‐old biliary atresia child

Abstract: We present a case of a 10‐month‐old boy with BA who developed HCC and was treated with liver transplantation. A four‐month‐old boy was referred to our institution because of persistent jaundice, hepatomegaly, and coagulopathy. He had been treated for the diagnosis of neonatal hepatitis at an outside hospital. He was evaluated and was accepted as a liver transplant candidate, and was subsequently transplanted with a deceased donor liver allograft at the age of 10 months. His native liver showed established cirrhosis because of BA with one focus of moderately differentiated HCC, measuring 0.7 cm in a diameter with microscopic vascular invasion in pathological study. The postoperative course was uneventful, and he is well without recurrence four months after liver transplantation. The occurrence of HCC in a child under one yr old is extremely rare, and only three cases are reported so far including our case.     

Epstein‐Barr virus DNA monitoring in serum and whole blood in pediatric liver transplant recipients who do or do not discontinue immunosuppressive therapy

The rate of PTLD can be reduced by weaned IS guided by monitoring of EBV DNA. In this single‐center retrospective case series study, we analyzed how reduction in IS influenced EBV DNA levels in whole blood and serum in 30 children during the first year after liver transplantation, and how these levels were related to symptoms putatively due to EBV. Primary and reactivated EBV infection was seen in 18 (60%) and eight patients (27%), respectively. Thirteen patients (42%) developed chronic high load the first year post‐transplant. IS was successfully discontinued in six patients the first year post‐transplant and in another two patients within 3 years. EBV DNA levels were reduced, but persisted long term in all the eight patients who had IS completely withdrawn. There was no case of PTLD. In summary, EBV DNAemia and chronic high load were very common after pediatric liver transplantation. Liver graft tolerance facilitates radical reduction in IS treatment, which may prevent PTLD, but EBV DNAemia may persist long term after discontinued IS.     

AST‐to‐platelet ratio index in non‐invasive assessment of long‐term graft fibrosis following pediatric liver transplantation

Long‐term graft fibrosis occurs in the majority of pediatric liver transplant recipients. Serial biopsies to monitor graft health are impractical and invasive. The APRI has been evaluated in pediatric liver disease, but not in the context of post‐transplantation fibrosis. We aimed to investigate the validity of APRI as a predictor of long‐term graft fibrosis in pediatric liver transplant recipients. This was a retrospective, observational study of a cohort of children who underwent liver transplantation at King's College Hospital between 1989 and 2003, with a relevant dataset available. Protocol liver biopsies were performed at 10‐yr follow‐up and fibrosis was graded using the Ishak scoring system, with S3‐6 denoting “significant fibrosis.” APRI was calculated concurrently with biopsy. A total of 39 asymptomatic patients (20 males; median age at transplant, 1.43 yr) underwent protocol liver biopsies at a median of 10.39 yr post‐transplantation. APRI was associated with significant fibrosis (p = 0.012). AUROC for APRI as a predictor of significant fibrosis was 0.74 (p = 0.013). The optimal cutoff APRI value for significant fibrosis was 0.45 (sensitivity = 0.67; specificity = 0.79; PPV = 0.67; NPV = 0.79). APRI appears to be a useful non‐invasive adjunct in the assessment of significant graft fibrosis in the long‐term follow‐up of pediatric liver transplant survivors.     

Successful living‐related renal transplantation in a patient with factor H antibody‐associated atypical hemolytic uremic syndrome

CFH‐Ab‐associated aHUS requires different diagnostic and therapeutic approaches and then the genetically defined aHUS forms. The risk of post‐transplant recurrence with graft dysfunction in CFH‐Ab aHUS is not well documented. It is suggested that recurrence can be expected if a significant CFH‐Ab load persists at the time of transplantation. A pretransplant procedure to reduce CFH‐Ab titer seems reasonable, but accurate recommendations are lacking. Whether further prophylactic interventions after transplantation are necessary has to be decided on an individual basis. We report the case of a late diagnosed CFH‐Ab HUS with initial ESRD and a successful living‐related renal transplantation over a post‐transplant period of four and a half years on the basis of a prophylactic pretransplant IVIG admission.     

Cysteamine in renal transplantation: A report of two patients with nephropathic cystinosis and the successful re‐initiation of cysteamine therapy during the immediate post‐transplant period

Nephropathic cystinosis is a rare disorder causing the accumulation of intracellular cystine crystals in tissues. The damage to the proximal tubules of the kidneys results in Fanconi syndrome, and patients with cystinosis experience the progression of chronic kidney disease, resulting in the need for kidney transplantation. Treatment of cystinosis with cysteamine has proven to be effective; however, it has many gastrointestinal side effects that are concerning for transplant specialists during the immediate post‐transplant period. Transplant specialists routinely discontinue cysteamine therapy for up to six weeks to ensure proper immunosuppressant absorption. This practice is worrisome because it communicates the acceptability of lapses of cysteamine treatment to patients. It may be better to re‐initiate cysteamine therapy shortly after transplantation while the patient is followed more closely by the transplant team. This report presents two pediatric patients with nephropathic cystinosis who successfully restarted cysteamine therapy in the immediate post‐transplant period without issue in regard to immunosuppression absorption or gastrointestinal side effects. These cases challenge current practice of discontinuing cysteamine therapy during kidney transplantation, and immediate re‐initiation of cysteamine therapy in cystinosis patients post‐transplant should be considered.     

Isolated unilateral cytomegalovirus retinitis: A rare long‐term complication after pediatric liver transplantation

Squires JE, Sisk RA, Balistreri WF, Kohli R. Isolated unilateral cytomegalovirus retinitis: A rare long‐term complication after pediatric liver transplantation. Abstract: To highlight the rare yet devastating complication of CMV retinitis in a minimally immunosuppressed patient eight yr after liver transplantation for biliary atresia. A 22‐yr‐old female status‐post deceased donor liver transplant at age 13 secondary to biliary atresia receiving single agent immunosuppression presented with acute, unilateral, profound decrease in visual acuity. The patient was diagnosed to have acute onset unilateral CMV retinitis. Retinal examination uncovered classical appearance of retinal whitening and retinal hemorrhages with extensive macular involvement. CMV retinitis can occur as a late complication following liver transplantation. Additionally, CMV retinal disease can occur in the absence of laboratory evidence of CMV infection and independent of additional clinical features suggesting CMV disease. Currently, there is no standard of care regarding screening for CMV retinitis, and thus, further research is needed to define the need for potential changes in current clinical practices and post‐transplant screening protocols.     

The use of everolimus in pediatric liver transplant recipients: first experience in a single center

The role of mTOR inhibitors, such as EVL, has not been established for pediatric liver transplant recipients up to now, although data from adult solid organ graft transplantation are very promising. Major complications following pediatric liver transplantation in the long-term course include chronic graft rejection and CNI-derived nephrotoxicity. The purpose of our study was to report first results using EVL as a rescue therapy in pediatric liver transplant recipients for the following indications: chronic graft dysfunction n=12, suspected CNI toxicity n=3, hepatoblastoma n=2, and recurrence of primary sclerosing cholangitis post-Ltx n=1. Four patients with chronic graft dysfunction developed completely normal liver function tests using EVL, six patients showed partial improvement, and two patients did not respond at all. One patient with CNI-induced nephropathy showed a slightly improved GFR. Both patients with hepatoblastoma did not develop any metastasis post-Ltx. First experience with EVL in pediatric liver transplant recipients shows promising results in patients with chronic graft failure when standard immunosuppression has failed. The future role of EVL in immunosuppressive protocols for children post-Ltx has to be proven by controlled clinical trials.     

Size‐reduced lung transplantation in children – an option worth to consider!

Benden C, Inci I, Weder W, Boehler A. Size‐reduced lung transplantation in children – an option worth to consider!
Pediatr Transplantation 2010: 14:529–533. © 2009 John Wiley & Sons A/S. Abstract: Lung transplantation is an accepted therapy for pediatric end‐stage lung disease. However, there is a shortage of suitable donor organs. Therefore, the use of downsized lung allografts seems a valuable option. We report our experience of downsized pediatric lung transplantation in comparison with standard full‐size pediatric lung transplantation over one decade. Pediatric recipients undergoing downsized or standard lung transplantation were included (January 1997–December 2006). We compared pretransplant clinical data and surgical and post‐operative complications and post‐transplant outcome. Ten pediatric lung transplants were performed (median patient age 15.6 yr [12.3–17.8]). Nine of 10 patients had CF. Five patients underwent standard full‐size lung transplantation; five had downsized lung transplants. “Downsized” recipients had significantly lower median height and weight Z‐scores. Donor/recipient length difference was significantly greater in the “Downsized” Group (p < 0.05). All patients had comparable post‐transplant functional outcome without additional surgical complications or morbidities in “downsized” recipients. Median post‐transplant survival was 65 months (5–77) in the “Standard” Group compared to 86 months (64–121) in the “Downsized” Group (p = 0.1). Our data suggest that downsized lung transplantation in pediatric recipients may have post‐transplant outcomes comparable to full‐size lung transplantation without significant complications.