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Infantile hepatic hemangioma, the most common vascular tumor of the liver in infancy, can occur with acute postnatal liver and congestive heart failure. Nevertheless, its course is often benign, and many children can be diagnosed and treated without surgical intervention. The distinction from malignant diseases is not always easy and it not clear whether invasive procedures for diagnosis and therapy should be performed. Here we report our experiences in our Center for Pediatric Liver Disease and postulate that large studies are needed to avoid unnecessary invasive procedures for these patients in the future., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2020 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition.)

In primary hyperoxaluria type 1 (PH1), systemic oxalate deposition (oxalosis) in end-stage renal disease (ESRD) is associated with high morbidity and mortality, particularly in children with infantile oxalosis (IO). Combined liver and kidney transplantation (CLKT) is the only curative treatment option in these patients. After CLKT, systemic oxalosis decreases continuously, although only insufficient data are available regarding oxalate retinopathy (ROx), leading to severe visual impairment. We analyzed long-term follow-up data of ROx in 13 patients undergoing CLKT for PH1 at our center between 1998 and 2018. Age at transplantation was 1.3-14.2 years, including nine patients with IO. We performed visual acuity testing, slit lamp investigation, funduscopy, fundus photography, and spectral-domain optical coherence tomography (SD-OCT) imaging. Severe (grade 2-4) ROx was present in all nine children with IO but not in the four patients developing ESRD in adolescence. A significant negative correlation was found between age at onset of ESRD and grade of ROx (r = -0.66; P < .001). Notably, follow-up assessment after CLKT demonstrated no regression of ROx after a median of 5.3 years (range 0.6-14). The data show that despite early CLKT in IO, ROx is irreversible and the concomitant visual deterioration occurs prior to transplantation., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Combined liver-kidney transplantation (CLKT) in children is still a rarely performed procedure. Our aim was to analyze the effect of the simultaneous transplantation of the kidney in pediatric CLKT on the liver graft flow velocity, and vascular complications compared to singular liver transplantation (LTX) in children., Methods: All pediatric CLKT performed at our institution from 1998 to 2016 were matched with singular LTX and retrospectively analyzed., Results: Overall 30 CLKT were performed in 28 children (median age 8 years, range 1-16) and matched with 30 children undergoing singular LTX (median age 7.9 years, range 1-16). No significant differences were found concerning the systolic peak flow velocity of the hepatic artery (HA) or the resistance index (RI). Vascular complications of the hepatic vessels occurred in 16.7% (CLKT) and 6.7% (LTX). The 1-/5- and 10-year patient survival was 93.3%/93.3% and 93.3% (CLKT) and 100%/100% and 92.9% (LTX). 1-/5-and 10-year liver graft survival was 76.7%/73.2% and 73.2% (CLKT) and 84.4%/75.9% and 69.6% (LTX)., Conclusion: The simultaneous transplantation of the kidney in CLKT had no negative impact on hepatic flow velocity or vascular complications. Frequent Doppler ultrasound examinations, accurate volume management, and avoidance of abdominal pressure might be an explanation for the results and an excellent graft- and patient survival., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Assessing liver fibrosis in patients after liver transplantation is still largely dependent on liver biopsy. Especially in children, noninvasive methods are of utmost importance. We evaluated tissue inhibitor of metalloproteinase 1 (TIMP1) and AST-to-Platelet Ratio Index (APRI) and their potential as serum biomarkers to predict liver allograft fibrosis (LAF) in a pediatric cohort., Methods: In this retrospective, observational study, we analyzed 91 protocol liver biopsy specimens from 73 children after pediatric liver transplantation (PLT) and compared histological stage of liver fibrosis using LAF Score (LAFSc) and Ishak Score (IshakSc) to TIMP1-serum concentration and APRI using ROC analysis., Results: In our cohort, TIMP1 and APRI reliably predict LAF. Depending on the histological scoring system, cutoff values for TIMP1 were 328 ng/mL (IshakSc ≥ IV) and 351 ng/mL (LAFSc ≥ 5) with AUC of 0.86 and 0.98. The cutoff for APRI was 0.8 with AUC of 0.87 (IshakSc ≥ IV) and 0.94 (LAFSc ≥ 5). Using LAFSc, TIMP1 and APRI showed excellent diagnostic accuracy to detect severe LAF (LAFSc ≥ 5) with PPV of ≥ 90% and NPV of 100%., Conclusion: TIMP1 and APRI are accurate biomarkers to predict severe LAF in children. The use of TIMP1 and APRI will not replace but complement liver biopsies after PLT to further improve our understanding of each individual patient., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Hepatoblastoma is a rare malignancy but the most common primary hepatic malignancy in childhood. Pediatric liver transplantation (LT) offers the possibility to achieve a complete resection in otherwise unresectable tumors. Almost no data are available regarding specific surgical technique of LT in children with hepatoblastoma., Methods: We analyzed all children with hepatoblastoma and LT between 2007 and 2012. Special regard was given to the surgical technique and long-term follow-up., Results: Overall 7 children were transplanted with the diagnosis of hepatoblastoma (5 male, 2 female). Thereof, 4 children (median age was 11 months, range, 6-31 months) underwent "primary" LT for hepatoblastoma Pretreatment Extent of Disease III to IV. A 4-year-old boy received "salvage" LT for recurrent hepatoblastoma 2.5 years after successful liver resection. Another 15-year-old boy was transplanted as a prophylactic treatment after repeated liver resection for hepatoblastoma due to the high recurrence risk. A 14-year-old boy underwent LT due to complications following liver resection for hepatoblastoma during infancy. In all children, extensive en bloc hepatectomy was performed together with resection of the adjoining retroperitoneal tissue and regional lymphadenectomy. Actually, all children are alive without tumor recurrence median 7.1 years after LT (range, 5.7-10.7 years)., Conclusion: Our data show an excellent long-term outcome in selected children with hepatoblastoma undergoing standardized en bloc hepatectomy for "primary" and "rescue" LT with 100% overall and recurrence-free survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Liver transplantation (LT) has been shown to be a feasible treatment in patients with severe forms of maple syrup urine disease (MSUD). Because of a sufficient extrahepatic enzyme activity in non-MSUD individuals, the organ of MSUD patients can be used as a domino graft. We performed a retrospective data collection of all LTs for MSUD carried out at the University Medical Center Hamburg-Eppendorf (2016-2018). Moreover, data from all consecutive domino LTs of the MSUD grafts either transplanted at our institution or allocated to other transplant centers were analyzed. During the study period, 15 LTs in MSUD patients were performed (12 children, 3 adults; median age, 10.9 years; range, 0.3-26.1 years). Biliary complications occurred in 20%, and 13.3% suffered from bleeding complications. No further surgical problems occurred. At present, all MSUD patients are alive with a well-functioning liver graft and on an unrestricted diet. In total, 14 consecutive domino LTs were performed. No surgical complications requiring intervention occurred. One patient died because of HCC relapse, and all other patients are alive with good liver graft function. In conclusion, the use of MSUD livers as domino grafts is safe and allows application of LT in MSUD patients without net extraction of a liver graft from the limited donor pool., (Copyright © 2018 by the American Association for the Study of Liver Diseases.)

The aim of the study was to investigate the occurrence of fatigue in 100 pediatric liver transplant recipients aged 2-18 years and its impact on their health-related quality of life (HRQL). HRQL and fatigue were measured using the PedsQL 4.0 Inventory and the PedsQL Multidimensional Fatigue Scale, which encompasses three subscales: general fatigue, sleep/rest fatigue, and cognitive fatigue. The impact of the different domains of fatigue and of clinical and sociodemographic factors on the HRQL was identified with stepwise multiple regression analyses. Parent proxy-reports were available for all 100 participants (2-18 years), and child self-reports were available for 71 patients (8-18 years). Across all domains, participants and their parents reported significantly more fatigue than healthy peers in a large PedsQL validation study. Thirty-seven percent of patients and 57% of parents scored clinically relevant levels of fatigue. In the multiple regression analyses, none of the clinical and sociodemographic factors contributed to the HRQL for child self-report. Only general and cognitive fatigue were significant predictors of patients' HRQL, explaining 66% of the variance in the PedsQL total score. For parent proxy-report, general and cognitive fatigue also significantly predicted child's HRQL. Further predictors were child's age and family income. The regression model explained 65% of the variance. These findings demonstrate the importance of assessing fatigue during regular follow-up examinations. Further research is urgently needed to better understand the underlying mechanisms of fatigue. Improvement of fatigue symptoms is essential for better HRQL, for cognitive functioning, and for school achievement., (© 2018 Wiley Periodicals, Inc.)

Objectives: Bile salt export pump (BSEP) deficiency is an important reason for chronic cholestasis leading to liver transplantation (LT) in early childhood. The underlying pathology is a dysfunction of BSEP due to various mutations in the ABCB11 gene. Cases of clinical recurrence after LT due to alloantibodies directed against BSEP (antibody-induced BSEP deficiency [AIBD]) have been reported. Most of these patients could be controlled by intensified immunosuppression., Methods: We here report on 3 children with BSEP-deficiency and end-stage liver disease, which developed AIBD after LT refractory to extensive immunosuppressive and immunomodulatory treatments; retransplantation was necessary in all 3 patients. In 1 patient, a stem cell transplantation was performed successfully., Results: AIBD seems to be induced by triggering factors such as initial impaired graft function or infections after LT., Conclusions: The underlying mutation may play a role in this process. Intensifying immunosuppression may be able to control AIBD, but some cases seem to be refractory to treatment and require retransplantation. Stem cell transplantation may provide a new therapeutic option for cases refractory to conservative treatment.

Progressive familial intrahepatic cholestasis 2 is an autosomal-recessive disorder caused by mutations in the ABCB11 gene, which encodes the bile salt export pump (BSEP). Recurrence of BSEP deficiency after liver transplantation is caused by the development of anti-BSEP antibodies. Antibody-induced BSEP deficiency is typically treated by increasing immunosuppressive therapy. We report, in a child, the first case of allogeneic haematopoietic stem cell transplantation for antibody-induced BSEP deficiency that was refractory to intensive pharmacological immunosuppression and immunoadsorption. After haematopoietic stem cell transplantation, anti-BSEP antibodies were cleared from the patient's serum and later from the canalicular space of the liver graft., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction: Full-split liver transplantation (LTX) offers the possibility to expand the donor pool by utilization of one liver for two adults. The aim of our study was to analyze the long-term outcome in a large series and its applicability in the recent transplant era., Methods: We performed a retrospective analysis of all full-split LTX from deceased donors (1999-2015). Additionally, the potential of full-split LTX was retrospectively analyzed in all whole organ LTX recipients between 2006 and 2015 (after introduction of the MELD allocation)., Results: We performed 44 full-split LTX, thereof 82% before introduction of the MELD-based allocation system in Germany. Analysis showed highly selected recipients (median MELD score 8 points) and organ data (median donor age 30 years). 5- and 10-year patient survival rates after full-left and full-right LTX were 90.7%/90.7% and 85.2%/56.8% (P = .301), corresponding graft survival rates were 80.5%/80.5% in full-left grafts and 73.7%/36.8% in full-right graft (P = .198)., Conclusion: In the past, in case of strict donor and recipient selection, full-split LTX was a feasible method with a good outcome. Due to introduction of the national waiting list with a patient-oriented allocation based on the MELD score in 2006, full-split LTX seems to be not any longer applicable., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To compare hepatic 2D shear wave elastography (2D SWE) in children between free-breathing and breath-hold conditions, in terms of measurement agreement and time expenditure., Methods: A cohort of 57 children (12.7±4.3 years) who underwent standardized 2D SWE between May and October 2015 were retrospectively evaluated. Liver elastograms were obtained under free-breathing and breath-hold conditions and time expenditure was measured. Median stiffness, interquartile range (IQR), and IQR/median ratio were calculated based on 12, six, and three elastograms. Results were compared using Pearson correlation coefficient, intraclass correlation coefficient (ICC), Bland-Altman analysis, and Student's t., Results: Median liver stiffness under free-breathing and breath-hold conditions correlated strongly (7.22±4.5kPa vs. 7.21±4.11kPa; r=0.97, P<0.001). Time to acquire 12 elastograms with free-breathing was lower than that with breath-holding (79.3±32.5sec vs. 143.7±51.8sec, P<0.001). Results for median liver stiffness based of 12, six, and three elastograms demonstrated very high agreement for free-breathing (ICC 0.993) and for breath-hold conditions (ICC 0.994)., Conclusions: Hepatic 2D SWE performed with free-breathing yields results similar to the breath-hold condition. With a substantially lower time requirement, which can be further reduced by lowering the number of elastograms, the free-breathing technique may be suitable for infants and less cooperative children not capable of breath-holding., Key Points: • Hepatic 2D SWE performed with free-breathing yields results similar to breath-hold condition. • Benefit of the free-breathing approach is the substantially lower time requirement. • Lowering the number of elastograms can further reduce time expenditure. • Free-breathing 2D SWE is suitable in children with suspected liver disease.

Background & Aims: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity., Methods: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling., Results: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect., Conclusions: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype., Lay Summary: FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development., (Copyright © 2017. Published by Elsevier B.V.)

While reduced HRQOL following isolated organ transplantation has been previously reported, there are no data in the context of children following CLKT. Twenty-three children who underwent CLKT at our institution were included in the study. The indication for CLKT was PH1 in 13 patients and ARPKD in 10 patients. Quantification of HRQOL was facilitated through the use of the PedsQL 4.0 Generic Core Scale. The results of the study were compared to healthy children and published data of children who had undergone LTx or KTx. The CLKT samples' child self-report showed good HRQOL. No statistically significant difference was found between the patients with PH1 and patients with ARPKD (P=.4). Compared to healthy children, a significant difference in the total scale score, the physical health score, and the school functioning was reported. HRQOL did not differ significantly when compared to patients following isolated LTx or KTx. To improve HRQOL after CLKT, a focus on patients' physical health, educational performances, and overall quality of life is crucial. Thus, coordinated medical care across disciplines and psychological and social support is essential to achieve this goal., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Persistently elevated eosinophil granulocytes in the peripheral blood in children is challenging because of a complex diagnosis especially after solid organ transplantation and can lead to difficulties in finding an underlying causative factor.We report a 12-year-old boy who developed severe hypereosinophilia 11 years after liver transplantation due to biliary atresia. Accompanying symptoms were recurrent fever, fatigue, elevated liver enzymes, abdominal pain, and significant weight loss. After exclusion of secondary causes of eosinophilia, an idiopathic hypereosinophilic syndrome (I-HES) was diagnosed. Treatment with prednisolone resulted in an immediate response with rapid reduction of eosinophils, normalization of liver enzymes, and amelioration of any clinical symptoms. A hypereosinophilic syndrome in patients after liver transplantation is rare, and a broad differential diagnosis has to be considered. Prednisolone may lead to a prompt amelioration of eosinophilia and associated symptoms.

Neuroblastoma (NBL) stage 4s is an incompletely understood phenomenon with variable clinical course. While the majority of patients may undergo spontaneous regression and achieve complete resolution without intensive therapy, a small proportion is at increased risk of developing secondary complications. One such situation is liver insufficiency due to diffuse metastases. We report a patient suffering from NBL 4S who required double lifesaving liver transplantation. Abdominal and respiratory complications due to hepatomegaly are crucial determinants for treatment intensity and duration in 4S NBL [1,2] . We provide an algorithm in order to facilitate the clinical decision when dealing with similar potentially life-threatening events.

Unlabelled: Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC-2 who developed PFIC-like symptoms after orthotopic liver transplantation (OLT). BSEP-reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody-induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC-2 patients who suffered from phenotypic disease recurrence post-OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G-class BSEP-reactive antibodies in these patients. In all cases, the N-terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C-terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle-based functional assay, transport inhibition by anti-BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG., Conclusions: PFIC-2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post-OLT. The antibody response is polyclonal, targeting both extra- and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis., (© 2015 by the American Association for the Study of Liver Diseases.)

Background: Anti-HLA antibodies and especially donor-specific antibodies (DSA) play a significant role in graft survival after solid organ transplantation. Their impact on long-term survival in adult liver transplantation (LT) is controversial, but they may be a risk factor. The effects of DSA after pediatric LT are still unclear., Methods: We performed a retrospective evaluation of DSA in sera from 43 children who had received transplants at our tertiary center. Twenty-four patients had good long-term clinical and laboratory graft function (group 1), whereas 19 LT recipients suffered from histologically confirmed and clinically relevant chronic allograft rejection (group 2); 16 of these have already undergone retransplantation due to graft dysfunction. Inclusion criteria were availability of sera before the first LT to identify preformed antibodies in case of DSA positivity after LT and long-term follow-up at our institution. Sera were analyzed for anti-HLA antibodies using Luminex single antigen beads, where a mean fluorescence intensity value of more than 1500 was considered positive., Results: The prevalence of DSA was 33% for group 1 and 68% for group 2. Antibodies were predominantly HLA class II. Values of mean fluorescence intensity were comparable in both groups. Only one of the DSA+ ve patients from group 1 exhibited preformed antibodies. In conclusion, pediatric patients with chronic rejection revealed a higher rate of de novo DSA, especially of HLA-class II DSA. Further studies are necessary to confirm these data with a larger pediatric cohort.

Liver allocation in the Eurotransplant (ET) region has changed from a waiting time to an urgency-based system using the model of end-stage liver disease (MELD) score in 2006. To allow timely transplantation, pediatric recipients are allocated by an assigned pediatric MELD independent of severity of illness. Consequences for children listed at our center were evaluated by retrospective analysis of all primary pediatric liver transplantation (LTX) from deceased donors between 2002 and 2010 (110 LTX before/50 LTX after new allocation). Of 50 children transplanted in the MELD era, 17 (34%) underwent LTX with a high-urgent status that was real in five patients (median lab MELD 22, waiting time five d) and assigned in 12 patients (lab MELD 7, waiting time 35 d). Thirty-three children received a liver by their assigned pediatric MELD (lab MELD 15, waiting time 255 d). Waiting time in the two periods was similar, whereas the wait-list mortality decreased (from about four children/yr to about one child/yr). One- and three-yr patient survival showed no significant difference (94.5/97.7%; p = 0.385) as did one- and three-yr graft survival (80.7/75.2%; and 86.5/82%; p = 0.436 before/after). Introduction of a MELD-based allocation system in ET with assignment of a granted score for pediatric recipients has led to a clear priorization of children resulting in a low wait-list mortality and good clinical outcome., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In case of graft failure, re-LTX is the only life-saving option but it has been associated with inferior results. This study analyzes the outcome following pediatric re-LTX with a main focus on the timely relation between initial transplant and re-LTX. All pediatric LTX at our institution between 2000 and 2010 divided into patients with primary LTX and patients undergoing re-LTX early (≤30 days) or late (>30 days) after previous LTX were analyzed. Two hundred and ninety-eight primary LTX(79%), 33 early (9%), and 46 late (12%) re-LTX were performed. Patient/graft survival was significantly worse for children undergoing early re-LTX compared to primary LTX and late re-LTX (p = 0.024/0.001 and p = 0.015/0.03). One-/five-yr graft survival rates were 66%/49% for early re-LTX compared to 86%/76% for late re-LTX and 90%/74% for primary LTX. The inferior results in children undergoing early re-LTX were due to events occurring in the first six months with similar survival thereafter. No difference in outcome was evident after adjustment of the groups for high-urgency status. Outcome was excellent for primary LTX and late re-LTX, supporting late re-LTX in children. Early re-LTX takes an elevated risk of early graft loss and patient death; however, beyond the early postoperative period, the outcome was comparable., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Deoxyguanosine kinase (DGUOK) deficiency is a well-known cause of hepatocerebral mitochondrial DNA depletion syndromes, which include a broad spectrum of clinical presentations. Affected patients often develop life-threatening liver failure, but the benefits of liver transplantation (LT) are controversial because of the frequently severe neurological involvement due to the underlying mitochondrial disease. We describe the long-term clinical course of 2 patients from our institution and provide an update on their outcomes after LT with this condition. Another 12 pediatric patients were identified through a systematic search of the literature. All 14 reported patients underwent transplantation in infancy despite mild to moderate neurological impairment in some cases. The 2 DGUOK-deficient patients from our center displayed liver failure and mild to moderate neurological involvement. At the time of this writing, they had been followed for 5 and 8 years after LT, both patients were alive, and they had only mild neurological symptoms. Three of the 12 patients identified through the literature review survived for a long time (17, 12, and 23 years); 8 died during early follow-up; and for 1 patient, no follow-up information was available. The 1-year survival rate was 64%; 36% survived for more than 5 years. The long-term survivors had good quality of life. In conclusion, although survival after LT for DGUOK deficiency is lower than survival after LT for other indications, a significant proportion of patients benefit from LT with long-term survival and a stable neurological situation despite initial neurological abnormalities. Nevertheless, a decision to carry out LT for patients with DGUOK deficiency remains difficult because neurological symptoms may occur and worsen after LT despite their absence before transplantation., (© 2014 American Association for the Study of Liver Diseases.)

Purpose: We evaluated the feasibility of prenatal quantification of liver and spleen iron by magnetic resonance imaging (MRI) gradient recalled echo (GRE) measurements of transverse relaxation time (R2*) (MRI-GRE-R2*) in a fetal sheep model and applied the method to a human neonate with suspected neonatal hemochromatosis., Methods: We subjected 13 fetal sheep to MRI at 1.5 Tesla using a breath-triggered (ewe) multi-echo sequence to determine the transverse relaxation rate (R2*) of the liver and spleen. In the human neonate, we measured the R2* of the liver, spleen, and pancreas on the 30th postgestational day., Results: The median R2* of the fetal sheep liver was 25.6 s(-1) (range 20 to 114 s(-1)) and of the spleen, 40.2 s(-1) (range 20 to 70 s(-1)), and the corresponding median iron concentration in the liver was 0.85 mg/g dry weight (d.w.) and in the spleen, 1.22 mg/gd.w.. R2* rates in the human neonate liver were elevated between 67 s(-1) (average), which corresponded with an iron concentration of 1.9 mg Fe/gd.w., and 126 s(-1) (regional maximum), which corresponded with 3.4 mg Fe/gd.w.. The average pancreatic R2* (72.4 s(-1)) was significantly above normal values, which indicated iron overload., Conclusion: We demonstrated the feasibility of prenatal quantification of tissue iron by fetal MRI in this sheep model and successfully quantified iron, including that in the pancreas, in a human neonate to confirm the diagnosis of neonatal hemochromatosis. Transferring the successful approach of quantifying iron in intrauterine tissue in fetal sheep to human pregnancies with suspected fetal siderosis could aid early diagnosis.

Individualization of immunosuppressive medications is an important objective in transplantation medicine. Reliable biomarkers to distinguish between patients dependent from intensive immunosuppressive therapy and those where therapy can be minimized among pediatric transplant recipients receiving immunosuppressive medications are still not established. We evaluated the potential of cross-sectional quantification of regulatory T cells, lymphocyte subsets, and cytokine concentrations as biomarkers in 60 pediatric liver transplant recipients with AR, CR, or normal graft function and in 11 non-transplanted patients. Transplant recipients presenting with AR had significantly higher CD8+ T-cell counts, significantly higher concentrations of IL-2, and increased levels of IFN-γ compared with asymptomatic patients or controls. Regulatory T-cell numbers did not differ between children with rejection and children with good graft function. A tendency toward increased concentrations of IL-4 and TGF-β was detected in transplant recipients with good graft function. Cross-sectional parameters of peripheral regulatory T cells in pediatric liver transplant recipients do not seem to be valuable biomarkers for individualizing immunosuppressive therapy prior to the weaning process. Lymphocyte subsets, IL-2, IFN-γ, IL-4, and TGF-β serum concentrations may be helpful to identify children in whom immunosuppression can be reduced or discontinued., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Due to a lack of available size-matched liver grafts from children, most pediatric recipients are transplanted with technical variant grafts from adult donors. Size requirements for these grafts are not well defined, and consequences of mismatched graft sizes in pediatric liver transplantation are not known. Existing formulas for calculation of a standard liver volume are mostly derived from adults disregarding the age-related percentual liver weight changes in children. In this study, we aimed to establish a formula for general use in children to calculate the standard liver volume. In a second step, the formula was applied in pediatric patients undergoing liver transplantation at our institution between 2000 and 2010 (n = 377). Analysis of a large number (n = 388) of autopsy data from children by regression analysis revealed a best fit for two formulas: "Formula 1," children 0 to ≤1 year (n = 246): standard liver volume [ml] = -143.062973 +4.274603051 * body length [cm] + 14.78817631 * body weight [kg]; "Formula 2," children >1 to <16 years (n = 142): standard liver volume [ml] = -20.2472281 + 3.339056437 * body length [cm] + 13.11312561 * body weight [kg]. In comparison with children receiving size-matched organs, we found an elevated risk of liver graft failure in children transplanted with a small-for-size graft, whereas large-for-size organs seem to have no negative impact., (© 2013 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Liver transplantation offers excellent results for children with end-stage liver disease, and efforts should be directed toward maintaining long-term graft health. We evaluate graft pathology in healthy pediatric transplant recipients with low-maintenance immunosuppressive medications to assess whether protocol biopsies are helpful for adapting immunosuppression and protecting long-term graft function. Liver biopsies were performed on 60 healthy pediatric liver transplant recipients, and histological findings were correlated with laboratory, serological, and radiological results. Fourteen patients (23%) were diagnosed with acute or early chronic rejection, and immunosuppressive medications were increased in these children. Liver function tests did not correlate with histological findings. The incidence of fibrosis was 36% in transplant recipients five or more years after liver transplantation. We observed an unexpectedly high prevalence of rejection and fibrosis in children with no laboratory abnormalities, which led to changes in their immunosuppressive medications. Scheduled biopsies appear to be useful in pediatric transplant recipients with low immunosuppressive medications for early detection of morphological changes in liver transplants. Further studies are needed to evaluate whether adaption of immunosuppression helps to reduce tissue damage and the incidence of allograft dysfunction in the long term., (© 2013 John Wiley & Sons A/S.)

Amanita phalloides intoxication can lead to FHF with high mortality, especially in children. There is still ongoing discussion about the optimal treatment and decision criteria for emergency liver transplantation (LTx). Here, we summarize our experience with outcomes in five children. Five children with severe A. phalloides intoxication were treated at our tertiary center from 1995 to 2010 and studied retrospectively with respect to clinical and laboratory aspects that might help to decide between LTx or conservative therapy only. The findings are discussed with regard to recommended treatment and transplantation criteria for adults. All patients survived, of whom two of five received emergency LTx. Three patients survived with conservative treatment consisting of intravenous silibinin, NAC, detoxification measures, and intensive care. Indications for LTx in two children were progressive brain edema and cardiovascular failure. Children with FHF due to A. phalloides intoxication should be considered early for emergency LTx but should be monitored closely for the necessity of definite LTx. Early detoxification with active charcoal as well as silibinin and NAC seems to improve the outcome. Late recovery of liver function after day 4 post-ingestion is possible., (© 2013 John Wiley & Sons A/S.)

Outcomes of pediatric liver transplantation have constantly improved in the last decade. Living-related liver transplantation does not seem to improve long-term outcomes following liver transplantation, but few studies have evaluated immunological parameters of the alloimmune response after living vs. deceased donor organ transplantation. We analyzed numbers of regulatory T cells, lymphocyte subsets, and serum cytokine concentrations in 12 pediatric recipients of living-related liver transplants and in 28 pediatric recipients of deceased donor organs during their annual follow-ups. Transplant recipients who underwent living donor organ transplantation had significantly higher numbers of regulatory T cells and IL-4 serum concentrations than recipients of deceased donor organs; both of these factors are associated with beneficial outcomes and transplantation tolerance. Living-related liver transplantation may have potentially beneficial immunological aspects, although long-term outcomes do not seem to be better in recipients of living donor organs than in recipients of deceased donor organs. Further studies are needed to compare immunological aspects of the two transplant procedures., (© 2013 John Wiley & Sons A/S.)

In children with renal insufficiency and accompanying or underlying liver disease, combined liver and kidney transplantations (CLKT) are indicated. However, because of the rare indications, the number of paediatric CLKT is low. Our aim was to analyse CLKT in children with special regard to surgical aspects and outcome. All paediatric CLKT performed at our institution between 1998 and 2009 were retrospectively analysed. Between 1998 and 2009, 15 CLKT were performed in 14 paediatric patients (median age 8 years, range 1-16 years). The indications for CLKT were autosomal recessive polycystic kidney disease (n = 7), primary hyperoxaluria type 1 (n = 7) and retransplantation because of primary liver nonfunction (n = 1). In the postoperative course, six patients showed bleeding complications, thereof three patients needed operative revision for intra-abdominal bleeding. Eight of 15 patients (53%) needed dialysis. The 1- and 5-year patient survival was 100%; and 1- and 5-year graft survival was 80% for the liver and 93% for the kidney allograft. A number of different complications, especially secondary haemorrhage have to be anticipated after CLKT, requiring a timely and interdisciplinary treatment approach. With this management, our patients showed an excellent graft and patient survival., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)

FHF is characterized by a high percentage of unknown causes leading to acute liver failure and furthermore by an increased morbidity and mortality prior to and post-Ltx. In different transplant centers, the reasons leading to FHF differ significantly as well as outcome. We report our single center experience with 30 pediatric patients receiving a liver transplant for FHF, out of a total of 83 children presenting with FHF. The time to transfer patients to the transplant center after the diagnosis of FHF was long, with a median of 14 days (Ltx group) and 12 days (controls), respectively. In nearly half of the patients (n = 14) in the Ltx group, we were not able to establish an exact diagnosis prior to Ltx: 50% suffered from encephalopathy, and 13 patients were treated in the intensive care unit prior to transplant. Because of the availability of different surgical techniques, all children received a timely transplant [split (n = 18), living donor (n = 9), whole organ (n = 2), and reduced liver (n = 1)]. Patient survival was 93.4%, and graft survival was 83.4% for at least one yr follow-up. Severe complications following Ltx included three cases with aplastic anemia and one child suffering from systemic mitochondrial depletion syndrome. The survival of patients treated medically was 83%. We conclude that a strong focus should be made on early referral to a specialized center and on improvement of diagnostic tools to timely detect the underlying reason for FHF. Results following Ltx for FHF are good.

IHHE as the most common vascular tumor of the liver in infancy can present with acute postnatal liver and congestive heart failure. LTx may be a lifesaving option, but can be complicated by extrahepatic involvement and bleeding complications, especially in neonates. Here we discuss the benefit of LTx in cases of acute postnatal deterioration and massive extent of the hepatic tumor. Three infants with IHHE were transplanted at our institution between 2005 and 2007. Two were neonates with acute postnatal decompensation and progressive liver and heart failure within days. Treatment with steroids and chemotherapy was ineffective; resection surgery and interventional treatment were not considered appropriate. LTx was performed at the age of 7 and 24 days, respectively. An additional infant with a bilobar tumor that evolved more slowly was transplanted on day-of-life 56. Patients 1 and 2 had to be resuscitated during the LTx procedure because of massive bleeding and both died during the procedure. Patient 3 had a complicated post-operative course but is doing well one-yr post-LTx. Neonates with extended hepatic and extrahepatic involvement of IHHE should be evaluated carefully prior to LTx. Whenever possible, alternative interventional treatment options should be considered.

In adult liver graft recipients, it has been shown that certain chemokine polymorphisms (CCR5Delta32) may correspond to ischemic type biliary lesions leading to chronic graft dysfunction. The aim of our present study was to assess the importance of CCR5Delta32 polymorphism in a cohort of pediatric liver graft recipients with regard to acute or chronic graft dysfunction. A total of 137 children post-liver transplantation have been included for genetic analysis (CCR5Delta32 polymorphism), and the incidence of acute and chronic graft dysfunction was analyzed. The most common diagnosis leading to LTx was biliary atresia (56.2%), the median age was 14 months, and 33.5% of the patients received a living-related graft. In all, 110 of the subjects were found to have the CCR5 wild type, 25 children were heterozygous for CCR5Delta32, and two patients were homozygous. Of 137, 44 (32.1%) developed acute graft rejection, nine out of 137 (6.6%) chronic graft dysfunction (vanishing bile duct syndrome), and 84 (61.3%) children had neither acute nor chronic graft rejection. There was no significant correlation between acute graft rejection or chronic graft dysfunction and the CCR5Delta32 allele in the study population. We conclude that CCR5Delta32 polymorphism may not play a role in acute or chronic liver graft dysfunction in children.

Background: Acute neonatal liver failure is a rare condition that is often fatal. Liver transplantation (LTx) in affected neonates may be life saving, but there are only few data on the long-term outcome of neonatal LTx., Patients and Methods: We conducted a retrospective study of 11 LTx performed in 10 pediatric patients with acute liver failure in the first month of life. Median age at LTx was 15 days (range: 7-31 days) and median weight was 3.25 kg (range: 2-4 kg). The reasons for liver failure were neonatal hemochromatosis (n=5), hemangioendothelioma (n=2), infection caused by echovirus type 11 (n=1), mitochondrial disorder (n=1), unknown (n=1), and primary nonfunction after LTx (n=1). In 10 patients, LTx organs of deceased donors were used (reduced size n=5, split n=5), and living donor LTx was performed in one neonate. The patients were evaluated with respect to survival, graft function, perioperative complications, and neurodevelopmental outcome., Results: After a median follow-up time of 5 years (range: 1-14 years), 8 of 10 patients (80%) were alive. Seven of them were in good clinical condition and had normal liver function tests. One patient had to undergo retransplantation because of primary nonfunction and another is currently listed for retransplantation because of chronic graft dysfunction. Neurodevelopment was normal in 75% of the surviving patients., Conclusions: Liver transplantation provides good short- and medium-term results in neonatal acute liver failure.

Progressive familial intrahepatic cholestasis (PFIC) is caused by mutations of the bile salt export pump or the multidrug resistance P-glycoprotein, resulting in chronic hepatic failure. Partial external diversion of bile or ileal bypass is effective in some cases and, in others, liver transplantation (OLT) is necessary. Forty-two children were included in this study. Twenty-six children suffered from PFIC type 2 and 16 from PFIC type 3. Symptoms included pruritus, cholestasis, liver cirrhosis, and growth retardation. Seventeen patients received external biliary diversion. Ten had to undergo OLT in the following course. As of this report, three of the remaining patients were on the wait list for OLT. Twenty-three children received a liver graft primarily with excellent outcome. Our data show that OLT is the option of choice in symptomatic PFIC and whenever liver cirrhosis is present. We suggest a very restrictive recommendation of external biliary diversion. However, gene therapy may be a future option for children with PFIC.

Background: The presence of autoantibodies and development of autoimmune hepatitis after liver transplantation has recently been reported as one of the causes for chronic graft dysfunction. The pathogenesis and clinical significance of this disease still remains unclear., Methods: We evaluate 96 patients for the prevalence of autoantibodies and autoimmune hepatitis after pediatric liver transplantation and review their clinical follow-up including virus serologies, ultrasound examination and liver biopsies., Results: Positive autoantibodies were detected in 74% of the patients after pediatric OLT. Graft dysfunction was observed in 46% of these children, and in 35% of the transplant recipients seronegative for autoantibodies. None of the patients showed histological signs or fulfilled clinical criteria for de novo autoimmune hepatitis. One child with negative autoantibodies was diagnosed to have a histologically proven de novo AIH two yr following OLT., Conclusions: There is a high prevalence of autoantibodies after pediatric OLT, but the incidence of de novo AIH is very rare. In transplant recipients showing elevated liver function tests de novo autoimmune hepatitis has to be excluded by liver biopsy even if the patient is seronegative for autoantibodies.

Both calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, are widely used in pediatric liver transplant recipients and currently data are limited with regards to long-term results using the one drug or the other in comparable low doses. We conducted the present study to assess the advantages and disadvantages of both drugs in children at least five yr post-liver transplantation. A total of 129 children were enrolled in the study. Thirty-eight of the children were switched to tacrolimus monotherapy for different reasons [steroid resistant graft rejection (n = 15), chronic rejection (n = 5), severe acute rejection (n = 4), repetitive acute graft rejection (n = 5), dysfunction of the transplant (n = 3), insufficient CsA metabolism (n = 3), hypertrichosis (n = 2), and CsA toxicity (n = 1)], four patients had primary tacrolimus therapy, and 87 patients are receiving cyclosporine. Mean trough levels were 5.3 +/- 2.3 ng/mL (tacrolimus) and 73.6 +/- 44.5 micro/L (cyclosporine), respectively at least five yr post-orthotopic liver transplantation (OLT). There was no significant difference in the calculated glomerular filtration rate between children on cyclosporine and tacrolimus (142.7 + 39.5 mL/min/1.73 m(2) vs. 151.1 +/- 44.1 mL/min/1.73 m(2)). The incidence of arterial hypertension was 7.1% vs. 9.2%, that of hepatotoxicity was 0% vs. 2.3%. Cosmetic changes were found in more than one-third of the patients on cyclosporine and in 4.8% of the patients receiving tacrolimus. Quality of life was excellent in both groups (self assessment). The impact of CNIs on chronic graft dysfunction cannot be assessed by our present study. We conclude from the results that cyclosporine and tacrolimus are both excellent drugs for maintenance immunosuppression in the long-term course following pediatric liver transplantation. However, this retrospective analysis is limited by the bias between children on CsA as compared with patients receiving tacrolimus. A prospective randomized controlled trial is needed in order to assess which CNI is the best for children following OLT.

Objective: Neonatal hemochromatosis is a severe, often fatal multiorgan disorder of iron metabolism. Liver transplantation can be curative; the benefit of antioxidant treatment is discussed controversially. We summarize our experience with neonatal hemochromatosis over the past 13 years., Methods: A retrospective study was performed of 16 patients with acute liver failure attributable to neonatal hemochromatosis between 1992 and 2004., Results: Median age at the onset of neonatal hemochromatosis was 2 days (range: 0-21 days). Median weight at the time of diagnosis was 2900 g (range: 1520-4200 g). All patients had elevated ferritin levels (median: 4179 microg/L), and transferrin saturation (median: 99%). Fourteen patients (87.5%) showed significant hepatocyte siderosis in biopsies; 4 children had additional iron deposition in extrahepatic tissue. Four patients were diagnosed by MRI. Seven infants received liver transplants, 5 of them in combination with a preceding antioxidant treatment. Four children (25%) received antioxidants without the necessity of liver transplantation and were in good clinical condition at the time of this evaluation. Five patients (31.3%) died, 3 of them without any treatment because of initial fulminant multiorgan failure. In September 2005, 68.7% of the patients were still alive after a median follow-up of 5 years., Conclusions: Neonatal hemochromatosis is a severe metabolic disease, but early antioxidant treatment and liver transplantation in addition to optimal medical care can improve the outcome dramatically. Children with moderate liver failure can survive without liver transplantation, but should be monitored closely for deterioration.

Several factors may contribute to post-transplant cholestatic complications after liver transplantation. These include ischemic reperfusion injury, hypoperfusion, bile duct strictures, and hepatotoxic drugs. Up to now, there have been no publications on tacrolimus cholestatic toxicity in clinical transplantation when the drug was used in therapeutic doses. We describe six pediatric liver graft recipients in whom cholestatic complications developed under a tacrolimus-based immunosuppression following liver transplantation and all of them suffered from previous steroid-resistant graft rejection. The overall incidence of cholestatic syndrome was 5.4% in children receiving tacrolimus. The immunosuppression was switched back to cyclosporine and prednisolone in all six patients resulting in completely resolved clinical signs and laboratory findings. We conclude from our observations that a cholestatic syndrome following pediatric liver transplantation may be caused by tacrolimus therapy following steroid-resistant graft rejection, even if given in therapeutic doses.

An AGS is a dominant inherited multisystem disorder caused by mutations in the Notch signaling pathway (JAG1). In our center, 5.3% of liver transplantations (OLT) are performed in children with AGS. Some of the affected children fulfilled criteria for OLT, despite the absence of liver cirrhosis. The aim of our present study was to evaluate the indications and outcome for OLT in children with this complex disorder as clear criteria are difficult to establish in clinical practice. A total of 37 patients were included in a retrospective analysis. Twenty-four children underwent OLT for chronic end-stage liver failure (n = 8) or symptomatic liver disease (n = 16). Patient survival post-OLT was 91.7% after 1 yr, that of graft survival was 87.5%, respectively. Significant post-transplant vascular complications included a mid-aortic syndrome (n = 1) and severe lethal bleeding due to suspected vascular malformation (n = 1). Severe hypercholesterolemia (>800 mg/dL) and xanthomata resolved completely in affected patients. We conclude from our data that indications for OLT in AGS should be extended to patients with severe symptomatic liver disease, even in the absence of liver cirrhosis because of the significantly improved outcome after pediatric OLT in the last decade. Future studies must identify underlying mechanisms of hypercholesterolemia and vascular malformation.

It has been shown that an induction therapy with the monoclonal anti-interleukin-2 receptor antibody basiliximab (Simulect) is capable to reduce the incidence of acute graft rejection in adult and pediatric liver transplantation (Ltx). However, data on long-term results using basiliximab in children post-Ltx are still pending. Therefore, the objective of our study was to report on the long-term results of basiliximab induction therapy in pediatric liver transplant recipients. A total of 54 children received two single doses of basiliximab in addition to cyclosporine and prednisolone following Ltx. We analyzed the incidence of acute and chronic graft rejection that of post-transplant lymphoproliferative disease (PTLD), and patient and graft survival. The follow-up was 22-46 months. The historical control group (matched controls) consisted of 54 patients treated with a cyclosporine and prednisolone dual therapy. Patient survival was 53 of 54 in the treatment group and 51 of 54 in the controls. One patient was retransplanted in the treatment group vs. three patients in the control group. The incidence of acute graft rejection was 16.6% compared with 53.7% in the control group (p < 0.001), that of chronic rejection was comparable in both groups (one of 54 vs. one of 54). The incidence of steroid resistant rejection was four of 54 vs. six of 54 that of PTLD were one of 54 vs. zero of 54. There were no adverse effects observed, which could be related to the antibody treatment. We conclude that basiliximab provides safe and effective induction immunosuppression in pediatric liver graft recipients. Short- and even long-term results are excellent.

Background: Despite major surgical and medical advances, it is still a challenge to perform transplantation in small infants. This study, focusing on short- and long-term outcomes, summarizes our 10-year experience with liver transplantation (LTx) in infants aged less than 6 months., Patients and Methods: We analyzed 43 patients aged 6 months or less (range: 12-184 days, median: 136 days) whose median weight at the time of LTx was 5.8 kg (range: 2.8-8.0 kg). The reasons for LTx were biliary atresia (n=27; 62.8%), neonatal hepatitis (n=6; 14%), neonatal cholestasis (n=4; 9.3%), and miscellaneous (n=6; 14%). The patients were followed up for a median time of 3 years and evaluated with respect to graft function, physical, and neurodevelopmental outcome., Results: The patient survival was 90.7% after 1 year and 87.2% after 2 years. The graft survival was 86% after 1 year and 82.1% after 2 years. Twelve patients (27.9%) experienced 15 surgical complications requiring intervention, two of whom demonstrated vascular thrombosis (4.7%). Acute early rejection occurred in 15 patients (34.9%), and chronic rejection occurred in 3 patients (7%); 83.3% of the patients had normal liver function test results at the time of evaluation. Complications such as posttransplant lymphoproliferative disease (4.7%) and persistent arterial hypertension (4.7%) were rarely seen. The physical and neurodevelopmental outcomes were good., Conclusions: LTx in infants aged less than 6 months provides excellent short- and long-term results. Low weight or young age of infants awaiting LTx should not be exclusion criteria for LTx.

Saliva antibodies to Escherichia coli O157 were investigated as markers of the immune response in children with enteropathic hemolytic uremic syndrome (HUS). Paired serum and saliva samples were collected from 22 children with HUS during acute disease and convalescence and were tested for E. coli O157 lipopolysaccharide (LPS)-specific IgM and IgA antibodies by ELISA. Serum and saliva samples from 44 age-matched controls were used to establish the cut-off values. Elevated levels of IgM and/or IgA antibodies to O157 LPS were detected in saliva of 13/13 HUS patients with Shiga toxin-producing E. coli (STEC) O157 in stool culture and from 4 of 5 HUS patients in whom STEC were not detected. These results closely mirrored the results obtained with paired serum samples. In contrast, saliva and serum samples from four children with STEC isolates belonging to O-groups O26, O145 (n = 2), and O165 lacked detectable O157 LPS-specific antibodies. The specificity of the ELISA was confirmed by western blotting. In STEC O157 culture-confirmed cases, the sensitivity of the ELISA was 92% for saliva IgM and IgA, based on the first available sample, and 100% and 92%, respectively, when subsequent samples were included. The specificity was 98% for IgM and 100% for IgA. Children with E. coli O157 HUS demonstrate a brisk, easily detectable immune response as reflected by the presence of specific antibodies in their saliva. Saliva-based immunoassays offer a reliable, noninvasive method for the diagnosis of E. coli O157 infection in patients with enteropathic HUS.

A 14-week-old boy with undiagnosed Chediak-Higashi syndrome developed fever with a high temperature and acute cardiac failure after having received a scheduled vaccination. We hypothesize that decreased concentrations and receptor binding of serum and tissue diadenosine polyphosphates, such as AP4A, AP5A, or AP6A, which are stored in various tissues and serve as extra-cellular signaling molecules or are secreted by cells in response to physiologically stressful stimuli, lead to the observed severe tachyarrhythmia. Diadenosine polyphosphates normally have a negative chronotropic and inotropic effect. This is the first report of severe cardiac failure in a child with Chediak-Higashi syndrome and we suggest that cardiac arrhythmias should be considered in such children in the event of high fever. Our hypothesis requires further investigation in other patients.