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Background: Asthma diagnosis may be challenging particularly in patients with mild symptoms without an obstructive pattern in spirometry. Detection of airway hyperresponsiveness (AHR) by a positive methacholine challenge (MCC) is still an important diagnostic tool to confirm the presence of asthma with reasonable certainty. However, it is time consuming and could be exhausting for patients. We aimed to identify the predictive factors for AHR in children with respiratory symptoms without obstructive pattern in spirometry. Methods: Data from children who had undergone MCC were analyzed retrospectively. The demographic features of patients along with laboratory results were collected. Results: A total of 123 children with a median age of 10.5 years were enrolled. AHR was detected in 81 children (65.8%). The age of the children with AHR was significantly younger. The prevalences of aeroallergen sensitization, nocturnal cough, wheezing, and a baseline forced expiratory flow at 75% of vital capacity (FEF75) 75 Conclusion: In children suspected of having asthma, but without an obstructive pattern in the spirometry, combining independent predictors, which can be easily obtained in clinical practice, might be used to identify children with AHR.

Background Nephrotic syndrome (NS) is one of the most frequent occurring chronic kidney diseases in childhood, despite its rarely occurrence in the general population. Detailed information about clinical data of NS (e.g. average length of stay, complications) as well as of secondary nephrotic syndrome (SNS) is not well known. Methods A nationwide ESPED follow-up study presenting the clinical course and management of children with NS in Germany. Results In course of 2 years, 347 children developed the first onset of NS, hereof 326 patients (93.9%) had a primary NS, and 19 patients had a SNS (missing data in 2 cases), the majority due to a Henoch-Schönlein Purpura. Patients with steroid-resistant NS (SRNS) stayed significantly longer in hospital than children with steroid-sensitive NS (25.2 vs. 13.3 d, p

BackgroundNeonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLI-similar 3 coding gene GLIS3. Almost 20 patients have been reported to date, with significant phenotypic variability.Case presentationWe describe a boy with a homozygous deletion (exons 5-9) in the GLIS3 gene, who presents novel clinical aspects not reported previously. In addition to neonatal diabetes, congenital hypothyroidism and other known multi-organ manifestations such as cholestasis and renal cysts, he suffered from hyporegenerative anemia during the first four months of life and presents megalocornea in the absence of elevated intraocular pressure. Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove. Considering reports on persistent fetal hemoglobin detected in a few children with GLIS3 mutations, the transient anemia seen in our patient may represent a further symptom associated with either the GLIS3 defect itself or, secondarily, micronutrient deficiency related to exocrine pancreatic deficiency or cholestasis.ConclusionsOur report expands the phenotypic spectrum of patients with GLIS3 mutations and adds important information on the clinical course, highlighting the possible beneficial effects of pancreatic enzyme and antioxidative vitamin substitutions on characteristic NDH syndrome manifestations such as TSH resistance and cholestasis. We recommend to carefully screen infants with GLIS3 mutations for subtle biochemical signs of partial exocrine pancreatic deficiency or to discuss exploratory administration of pancreatic enzymes and antioxidative vitamins, even in case of good weight gain and fecal elastase concentrations in the low-to-normal range.

Background: Methacholine challenge (MCC) is the most common method to detect airway hyperresponsiveness (AHR). Although MCC is accepted as safe diagnostic tool, it is time consuming and could be exhausting for patients. Thus, it might be helpful to identify predictive factors for AHR. We aimed to develop a diagnostic tool for predicting AHR in children with respiratory symptoms without obstructive pattern. Methods: Data from children who had undergone MCC were analyzed retrospectively. The demographic features of patients along with laboratory results were collected. Results: A total of 123 children with a median age of 10.5 years were enrolled. AHR was detected in 81 children (65.8%). The age of the children with AHR was significantly younger. The prevalences of aeroallergen sensitization, nocturnal cough, wheezing and a baseline forced expiratory flow at 75% of vital capacity (FEF75)

Some malignancies such as hepatoblastoma may be an indication for liver transplantation (LT) or some, for example, post-transplant lymphoproliferative disease (PTLD) may develop after successful LT. An immunosuppressive therapy after LT can promote the recurrence of the primary malignancy. The mammalian target-of-rapamycin inhibitors (mTORi) are immunosuppressive agents with anti-tumor properties. We examined the impact of everolimus (EVL) together with calcineurin inhibitors on allograft outcome and patient survival in pediatric LT (PLT) with various tumors. This retrospective study included eleven liver-transplanted pediatric patients who received EVL after LT. The reason for adding an mTOR inhibitor was the neoplastic disease, either leading to LT (n = 7) or PTLD that developed after LT under immunosuppression (n = 3). The median age at the start of therapy was four years (range: seven months- 18 years); the median follow-up was 3 (range: 1 – 5) years). The primary endpoints were recurrence or metastasis of the primary tumor, uncontrolled PTLD, or death. Graft function and potential side effects were documented. Both patient survival and graft survival rates for the observation period were 100%. No patient developed recurrence or reported metastatic disease of the primary tumor. Liver function test results remained normal during the study period in 8 out of 11 patients. Three patients developed elevated liver enzymes that resolved over time. All the patients received EVL either as monotherapy (n = 2) or in combination with cyclosporine A (n = 7) or tacrolimus (n = 2). Typical side effects documented were recurrent infections (n = 8), stomatitis (n = 5), and cytopenia (n = 2), and medication was temporarily interrupted in one patient. Although the patient cohort was small, our results support the use of EVL in patients with tumor occurrence in the context of pediatric LT. No cases of recurrence or metastases were reported during the follow-up period after LT; sufficient immunosuppression was maintained. The side effect profile appeared acceptable. A longer follow-up in more number of patients is necessary to confirm these preliminary data.

BACKGROUND The aim of this study was to investigate the association of serum periostin levels with clinical features in children with asthma. METHODS Children with physician-diagnosed asthma who attended regularly to an outpatient pediatric allergy and asthma center were enrolled in the study along with control subjects. Asthma severity and control status of the patients were evaluated according to the recent GINA guidelines. RESULTS A total of 158 children (125 with asthma and 33 age- and sex-matched control subjects) with a median age of 10.2 years (range 5.9-17.0) were enrolled. Asthma severity was mild in 41 (32.8%), moderate in 63 (50.4%), and severe in 21 (16.8%) children. Children with asthma had significantly higher periostin levels than controls (53.1 ± 13.1 vs 43.0 ± 11.2 ng/mL, P

Background: Periostin has emerged as a novel biomarker in the pathogenesis of T helper 2-type allergic diseases in the last years. The aim of this study was to investigate the association of serum periostin levels with clinical features in children with asthma. Methods: Children with physician-diagnosed asthma who attended regularly to an outpatient pediatric allergy and asthma center were enrolled in the study along with control subjects. Asthma severity and control status of the patients were evaluated according to recent GINA guidelines. Results: A total of 158 children (125 with asthma and 33 age and sex-matched control subjects) with a median age of 10.2 years (range 5.9-17.0) were enrolled. Asthma severity was mild in 41 (32.8%), moderate in 63 (50.4%) and severe in 21 (16.8%) children. Children with asthma had significantly higher periostin levels than controls (53.1 ± 13.1 vs 43.0 ± 11.2 ng/mL; p < 0.001). The mean serum periostin levels of children with severe asthma (63.8 ± 10.8) were significantly higher than in children with moderate asthma (53.3 ± 12.7) and mild asthma (47.4 ± 11.1) (p < 0.001). Serum periostin levels were found to be significantly correlated with asthma severity (Spearman’s rho [r]=0.41, p < 0.001). Results of multivariable logistic regression analysis demonstrated an association between serum periostin levels and asthma severity in children (OR, 1.10; 95% CI, 1.04-1.15; p

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications. Copyright © 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

The incidence of childhood nephrotic syndrome (NS) in Germany is not well known. An ESPED-based nationwide collection of epidemiological data of children in 2005 and 2006. The mean age of NS at onset was 5.5 ± 3.7 years. The gender ratio of boys to girls was 1.8:1. The average length of stay was 15.5 ± 11.2 days, with younger children remaining significantly longer in hospital. Steroid-resistance was more common in children ≥8 years (p = 0.023). Focal-segmental glomerulosclerosis (FSGS) was more common in children >10 years (p = 0.029). The ratio of males to females with FSGS was 1:1.9, thus the FSGS risk for girls at onset was 3.3-times greater. Considering the available data, the incidence of NS in Germany is 1.2/100,000 in the population

We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease-associated genes by a next-generation sequencing (NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor-like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold-induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor-like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1-related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing.

There is an increase of inactivity and overweight in children and adolescents which has a negative impact on their physical, motoric, emotional and cognitive development. This study examines changes in physical fitness and psychological well-being after participation in an intervention program offering a weekly professionally guided judo practice especially for overweight and obese children and adolescents. 26 overweight or obese children and adolescents (age 7 - 14) completed on average 28 sessions of judo training over a course of 12 months. Subjects completed a physical examination (stability, body composition, leg strength) and an assessment of psychological well-being (health-related quality of life, mental health problems) prior to entering the study, after 6 months and after completion of the training. We found significant changes in stability (p < .001), fat free mass (p = .001), leg strength (left p = .022, right p = .019), mental health problems (p < .001), conduct problems (p < .001) and peer problems (p < .001) and a trend in health-related quality of life (p = .055). Participants that dropped out (n = 12) showed a significantly higher BMI (p = .018) and higher scores in peer problems (p = .004). This study indicates that judo practice could have an influence on physical and psychological variables in overweight and obese children and adolescents. Judo provides a way to introduce regular physical activity among overweight and obese children and adolescents to support a more active lifestyle. We observed significant changes in physical fitness and psychological well-being in obese children after one year of judo practice. Approaches to support obese children in developing a more active lifestyle are of great significance.

ALG3-CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER-mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic data of four new ALG3-CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man5 GlcNAc2 -PP-dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right-descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3-CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open-reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP-ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect.

Objective Epistaxis in children is one of the most common causes for seeking professional medical help. Patients may be treated by several disciplines with various approaches to pediatric epistaxis. We reviewed cases of pediatric epistaxis from an otorhinolaryngologist's point of view. Methods A retrospective chart review was performed on all patients younger than 18 years presenting with epistaxis to the Department of Otorhinolaryngology at the University of Bonn, Germany. Results Sixty episodes of epistaxis in 58 patients were included in the study. Mean age was 10.1 ± 4.5 years. In terms of risk factors, 3 patients had a hemorrhagic diathesis, 3 had taken medication that interfered with hemostasis, and 8 had a history of previous trauma, most of which was digital manipulation. Twenty-six patients did not need invasive therapy. Twenty-six patients received cauterization to control the bleeding, and 4 patients needed surgery. The necessity for surgery was mainly noncooperation. Conclusions Epistaxis in children is seldom serious. However, hemorrhagic diathesis needs to be kept in mind as a potential cause of epistaxis. In most cases, careful instruction of the patients and the relatives concerning nasal mucosal care is sufficient. If cauterization is necessary, silver nitrate coagulation should be preferred over electrocoagulation.

Vor dem Hintergrund jungerer Publikationen zu moglichen Zusammenhangen zwischen dem Zeitpunkt der Beikosteinfuhrung und dem Auftreten von Nahrungsmittelunvertraglichkeiten nimmt die Ernahrungskommission der Deutschen Gesellschaft fur Kinder- und Jugendmedizin erneut zu dieser Frage Stellung. Bekraftigt wird die auf unterschiedlichen Erwagungen beruhende Empfehlung, Beikost nicht vor dem Alter von 17 Wochen und nicht spater als mit 26 Wochen einzufuhren. Dabei konnen zeitgleich auch Produkte mit starker allergener Potenz eingefuhrt werden. Eine fruhe Gluteneinfuhrung ab einem Alter von 17 Wochen reduziert nach aktuellem Kenntnisstand nicht das spatere Zoliakierisiko. Eine verzogerte Einfuhrung von glutenhaltigen Getreiden bei genetisch pradisponierten Kindern scheint die Zoliakiemanifestation zu verzogern, aber nicht zu verhindern. Eine Einfuhrung von Beikost mit starker allergener Potenz ab einem Alter von 17 Wochen konnte fur die Allergiepravention moglicherweise vorteilhaft sein, aber dies ist nicht hinreichend bewiesen. Unter Berucksichtigung von Mundmotorik, Nahrstoffversorgung, Allergiepravention und einer angemessenen Dauer des ausschlieslichen Stillens wird von einer Beikosteinfuhrung vor dem Alter von 17 Wochen ausdrucklich abgeraten.

Long-term outcomes of children with nephrotic syndrome have not been well described in the literature. Cross-sectional study data analysis of n = 43 patients with steroid-sensitive (SSNS) and n = 7 patients with steroid-resistant (SRNS) nephrotic syndrome were retrospectively collected; patients were clinically examined at a follow-up visit (FUV), on average 30 years after onset, there was the longest follow-up period to date. The mean age at FUV was 33.6 years (14.4–50.8 years, n = 41). The mean age of patients with SSNS at onset was 4.7 years (median 3.8 years (1.2–14.5 years), the mean number of relapses was 5.8 (0 to 29 relapses). Seven patients (16.3%) had no relapses. Eleven patients were “frequent relapsers” (25.6%) and four patients still had relapses beyond the age of 18 years. Except of cataracts and arterial hypertension, there were no negative long-term outcomes and only one patient was using immunosuppressant therapy at FUV. 55% of patients suffered from allergies and 47.5% had hypercholesterolemia. Two patients suffered a heart attack in adulthood. A younger age at onset (

Judo is a popular martial art and Olympic sport practiced in nearly every country of the world. With the increasing popularity and professionalism, skills of judo players have been improved together with the increasing frequency and seriousness of injuries. Judo is considered among the sports with the highest overall injury rate during competition. The upper extremity is more susceptible to injuries than the lower extremity. Depending on the definition of injury, accounting also for minor soft tissue trauma, the fingers are found to be the most common injured body part. Injuries to the fingers predominantly result from grip fighting, being thrown, and attempting to throw or during groundwork. Most acute incidents are lacerations on epidermal level, sprains, and strains, while more severe injuries as ligament or tendon ruptures, finger dislocations, and fractures are less frequently observed. Infections may result from superficial skin lesions. Repetitive microtrauma and overuse can lead to finger polyarthrosis. Most finger injuries are of minor severity and professional treatment is often not necessary. The athlete is rarely impaired in his judo career or daily living. Prevention of finger injuries includes taping of the exposed interphalangeal joints to protect the fingers from abrasions and being twisted. Constant adjustments of the official judo rules are important to exclude dangerous actions and techniques that present a high risk for injuries. Regular breakfall and throwing training should take place under closed supervision, especially for beginners and young judo players until a technique is mastered safely. Building up strength and conditioning also has a significant role in injury prevention.

In this review, we focused on CLKT with regard to indication, results, outcome, and future developments. PH1 is one of the most common diagnoses for adult and pediatric patients qualifying for CLKT. The other major indication for combined transplantation is ARPKD. CLKT appears to be superior to sequential liver and kidney transplantation in the majority of patients and overall results following CLKT are now good, even in small children. Clinical observations suggest that there is an immunological advantage of CLKT in comparison with isolated liver or kidney transplantation. More clinical studies are necessary to identify the best candidates for CLKT while the availability of donor organs is low.

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.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.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.

A 5-month-old girl developed intractable cerebral seizures and a global mental and motor retardation after a scheduled hexavalent vaccination. In the following years, recurrent fever, hepatosplenomegaly, and a pancytopenia indicated other organ system involvement. At the age of 4 years the diagnosis of a severe systemic autoimmune disorder was made, defined by highly elevated antinuclear antibody (ANA), smooth muscle antigen (SMA), extractable nuclear antigen, and decreased complement factors C3c and C4. Moreover, a low B cell count and an IgA and IgG2 subclass deficiency were found. After initiation of an immunosuppressive therapy as well as monthly intravenous immunoglobulin application, the clinical situation improved dramatically. Despite therapy and clinical improvement, there is still an intermittent elevation of ANA and SMA as well as decreased complement C4, a persistent low B cell count and an IgA deficiency. We propose the possibility of an underlying primary immunodeficiency with subsequent development of a severe systemic autoimmune disease possibly triggered by routine vaccination. The clinical features and laboratory tests are consistent with a systemic lupus erythematosus or lupus-like syndrome.

Background Congenital portosystemic shunts present with various associated complications, such as other congenital malformations, hyperammonemia, or hepatopulmonary syndrome. Few cases of associated hypoglycemia have been reported so far and our case, to the best of our knowledge, describes the most severe extent of hypoglycemia. Case presentation We describe the case of a newborn Arab boy with two intrahepatic portosystemic shunts, resulting in severe and persistent hypoglycemia, due to which one of the shunts was closed by interventional radiology whereas the other shunt had already closed spontaneously. Conclusions Because he showed elevated levels for insulin and prolonged high insulin levels in an oral glucose tolerance test, our case supports the theory that portocaval shunts cause a reduced hepatic insulin reduction due to the high blood volume bypassing the liver. This case provides further insights into glucose regulation mechanisms of the liver and we suggest a consistent screening for hypoglycemia in patients with congenital portosystemic shunts.

In a 24-month, multicenter, single-arm, prospective study, 56 pediatric liver transplant patients with or without basiliximab induction were converted at 1-6 months post-transplant from standard calcineurin inhibitor (CN) therapy (± mycophenolic acid), to everolimus with reduced exposure to CNI (tacrolimus n=50, cyclosporine n=6). Steroid therapy was optional. Recruitment was stopped prematurely due to high rates of PTLD, treatment-related serious infections leading to hospitalization and premature study drug discontinuation. Subsequently, patients aged

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.

To date, the course of cognitive development in children after liver transplantation (Ltx) is poorly understood. Cognitive performance, however, is crucial in all developmental stages and for educational achievement. This cross-sectional single-center study examined the prevalence of long-term cognitive impairment in a cohort of 64 pediatric patients after Ltx. Median age at Ltx was 12 months. The revised Wechsler Intelligence Scale IV was administered to assess cognitive performance. Patients were compared with an age- and gender-matched group of children without a chronic health condition. Liver transplanted children performed significantly worse in three of four cognitive domains as well as in the Total Intelligence Quotient (Total IQ) (p = 0.017 to p = 0.005). Liver transplant recipients showed substantially more "serious delays" (IQ 70) compared to the reference group (9.4% vs. 4.7%). Children with a genetic-metabolic disease performed worse than the other groups in three of the four WISC Indices and in the Total IQ (p = 0.05 to p = 0.01). The strongest association was revealed between height at Ltx and Verbal Comprehension (R(2) = 0.21), Perceptual Reasoning (R(2) = 0.30), Working Memory (R(2) = 0.23) and Total IQ (R(2) = 0.25). Our results indicate a high impact of primary diagnosis and height percentile at Ltx even on children's long-term cognitive performance.

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.

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.

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. (Hepatology 2016;63:524–537)

The use of everolimus has recently emerged for solid-organ transplantation in children. This review gives an overview of the relevant studies and clinical trials involving the immunosuppressive effects of everolimus in child organ transplant.The use of everolimus in pediatric organ transplantation is associated with a decrease in calcineurin inhibitor-related toxicity, better renal function, a low number of acute rejections, and an acceptable side-effect profile. Particularly, the use of everolimus reduces the incidence of virus infection and the risk of posttransplant lymphoproliferative disease.Everolimus is an effective agent with several advantages for pediatric solid-organ transplantation. Future prospective, randomized controlled trials will have to be performed in order to validate the findings of these pilot trials.

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.

Background Studies reporting the immediate pediatric intensive care unit (PICU) treatment after combined liver-kidney transplantation (CLKT) are scarce, although this period is pivotal for survival and long-term outcome. Methods We retrospectively analyzed all pediatric CLKT performed in our center between 1998 and 2010. Results Sixteen patients underwent 17 CLKT at a median age of 5.3 years (range, 1.3-15.9 years). Median body weight at CLKT was 17.7 kg (range, 9.2-55 kg). Underlying diagnosis was primary hyperoxaluria type 1 in nine patients and autosomal recessive polycystic kidney disease in seven patients. Median time on PICU was 8.5 days (range, 3-68 days); however, patients with primary hyperoxaluria type 1 had a significantly longer stay (P=0.031). Median duration of ventilation was 1 day; however, five patients required ventilation for 25 to 52 days. Continuous veno-venous hemofiltration was applied in nine patients due to delayed kidney graft function, volume overload, or high plasma oxalate. Overall, the survival rate after CLKT was 100% and long-term outcome was very good at a mean follow-up of 3.6 years (range, 0.5-12.2 years). Waiting time, donor age, and donor-to-recipient weight ratio were found to be significant risk factors for an extended PICU stay (P=0.02, 0.0031, and 0.014, respectively). Conclusions Immediate postoperative course after CLKT may be challenging and complex. However, excellent results can be achieved, even in small children.

Summary 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.

Summary Nowadays, most paediatric liver transplant recipients receive a split or other technical variant graft from adult deceased or live donors, because of a lack of available age- and size matched paediatric donors. Few data are available, especially for liver grafts obtained from very young children (

Kaller T, Boeck A, Sander K, Richterich A, Burdelski M, Ganschow R, Schulz KH. Cognitive abilities, behaviour and quality of life in children after liver transplantation. Pediatr Transplantation 2010: 14:496–503. © 2010 John Wiley & Sons A/S. Abstract: Aims: We investigated interrelations between cognitive abilities, behavioural problems, quality of life and disease-related variables of children after LTX. Methods: Our sample consisted of 25 children. They were 8.5/2.8 (M/SD) years old and had received the transplant 5.5/3.1 years previously. For assessment we used well-established instruments. Results: Liver transplanted children scored below the population mean on the cognitive as well as on the behavioural instrument and showed scores below average in the scales Self-esteem, Friends and Total Score regarding QoL. Behavioural problems were associated with poorer cognitive performance (r=−0.38 to −0.63). QoL regarding physical well-being was correlated with sequential processing (r=0.41). Lower sequential processing scores were associated with lower QoL. Also between behavioural parameters and QoL correlations could be determined. Children with more behavioural problems experienced lower QoL (r=−0.40 to r=−0.76). Age at onset of disease showed correlations with behavioural and QoL parameters (r=−0.49 resp. r=0.44). Cognitive functioning was associated with medical complications (r=−0.44). Conclusions: High interrelations between cognitive functioning, behavioural deficits and QoL were obtained. Especially noticeable are correlations between sequential processing and internalized behavioural functions as both are associated with left lateralized brain functioning. This relationship could indicate differential effects on brain development during the preoperative phase.

Little is known about the role of platelets in relation to ischemia/reperfusion injury (IRI) of the liver graft especially in children. Thrombocyte function was prospectively analysed in 21 consecutive pediatric liver transplantation (pLT) patients by platelet aggregometry secondary to adenosine diphosphate (ADP), collagen, and the von Willebrand factor activator ristocetin (VWF:rco). Post-OP serum levels of ALT were used to divide patients into groups with high (highHD, n = 8) and low (lowHD, n = 13) hepatocellular damage. Clinically, highHD-patients showed impaired plasmatic coagulation and elevated serum bilirubin levels early after pLT when compared with lowHD-patients. Further, platelet counts markedly decreased between pre-OP and postreperfusion (postrep.) in the highHD group (P = 0.003) and did not recuperate by POD6. In lowHD individuals thrombocytopenia improved from both pre-OP (P < 0.05) and postrep. (P < 0.001) respectively towards POD6. Experimental thrombocyte testing revealed that before graft reperfusion only ADP-dependent platelet aggregation correlated with reperfusion injury, thrombocytopenia and early graft function. During the first 48 h after graft reperfusion, all inducers tested demonstrated elevated platelet aggregation levels in the highHD group. Our data suggest a possible role of platelets and their aggregative status in liver IRI subsequent to clinical pLT. Reperfusion-independent ADP-triggered platelet function may be a determinant for IRI in the pediatric hepatic graft recipient.

Krampe K, Briem-Richter A, Fischer L, Nashan B, Ganschow R. The value of immunoprophylaxis for cytomegalovirus infection with intravenous immunoglobulin in pediatric liver transplant recipients receiving a low-dose immunosupressive regimen. Pediatr Transplantation 2010: 14: 67–71. © 2009 Wiley Periodicals, Inc. Abstract: The incidence of CMV infection following pediatric Ltx is particularly high, which can be attributed to the increased number of patients at high risk for primary infection (donor CMV+, recipient CMV−). Current approaches to cope with this complication producing post-operative morbidity include prophylactic or preemptive ganciclovir therapy. As the risk for symptomatic CMV infection is directly correlated with the intensity of immunosuppression, the aim of our study was to assess the value of IVIG in order to protect children receiving low-dose immunosuppression from CMV disease. Twenty-eight consecutive children (median age 62.2 months) at high risk prospectively received three infusions of IVIG on days four, 14, and 28 post-transplant and were monitored for six months post-Ltx. Immunosuppression consisted of cyclosporine (initial trough levels 170–200 μg/L) and prednisolone (starting dose 15 mg/m2) as well as basiliximab induction therapy. Patient survival was 100% and graft survival was 92.9%. Two subjects developed laboratory findings of CMV infection (8%) and one child suffered from tissue invasive CMV disease (4%). Three patients were excluded from the study because of protocol violations. We conclude that there was a low incidence of CMV disease among a prospective cohort receiving low-dose immunosuppression and a standard IVIG product.

BKV infection is a potential cause of renal dysfunction in non-renal organ transplant recipients. JCV is the causative agent of PML. Furthermore, polyomaviruses are tumor inducing viruses and molecular data suggest an association with malignancies among solid organ transplant patients. So far, there are no studies analyzing polyomavirus viruria following Ltx in children. We performed a prospective prevalence study at a mean of 2187 (range 20-5671) days after transplantation in 100 consecutive children admitted for the routine follow-up examination post-Ltx. The urine was screened for BKV and JCV DNA by using PCR in each case. A plasma analysis by PCR was also done if more than 100,000 DNA copies/mL urine were detected. BKV or JCV viruria was found in 19% (n = 19) of our patients. All patients were free of clinical signs of viral infection, PML, or nephropathy. GFR was normal in 97% of patients and we found no statistical difference of kidney function between patients with and without BKV/JCV viruria. The extent of immunosuppressive therapy had no influence on the polyomavirus viruria. Overall, we found a higher prevalence of polyomavirus viruria in our pediatric liver transplant recipients than reported in adult patients.

UNLABELLED We present a 4-year-old boy admitted to the hospital due to the typical symptoms of celiac disease with severe dystrophy, anaemia and elevated gliadin IgG antibodies. Upper endoscopy ruled out celiac disease but showed severe Candida esophagitis. Due to an impaired T-cell function especially following Candida antigen stimulation in vitro, plus recurrent Candida infections of the skin, the diagnosis of chronic mucocutaneous candidasis (CMC) was made. Under the treatment with fluconazol, trimethoprim/sulfmethoxazole and IVIG, the child improved impressively. Gliadin antibodies declined steadily. CONCLUSION The common symptoms growth retardation, anaemia and elevated gliadin antibodies are suggestive for celiac disease but very unspecific. The rare immunodeficiency CMC may cause elevated gliadin antibodies.