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Background Intestinal mucosal healing is nowadays preferred as the therapeutic endpoint in inflammatory bowel disease (IBD), but objective measurements at the molecular level are lacking. Because dysregulated mucin expression is suggested to be involved in mucosal barrier dysfunction in IBD, we investigated mucin expression in association with barrier mediators and clinical characteristics in colonic tissue of a pediatric IBD population. Methods In this cross-sectional monocentric study, we quantified messenger RNA (mRNA) expression of mucins, intercellular junctions, and cell polarity complexes in inflamed and noninflamed colonic biopsies from pediatric IBD (n = 29) and non-IBD (n = 15) patients. We then validated mucin expression at protein level and correlated mucin mRNA expression with expression of barrier mediators and clinical data. Results The expression of MUC1, MUC3A, MUC4, and MUC13 was increased in the inflamed colon of pediatric IBD patients compared with the noninflamed colon of non-IBD control subjects. Especially MUC13 mRNA expression associated with the expression of barrier mediators, including CDH1, OCLN, and TJP2. MUC1 and MUC3B mRNA expression in combination with calprotectin levels most accurately discriminated IBD patients from non-IBD control subjects (90.6% area under the receiver-operating characteristic curve [AUCROC], 92.0% sensitivity, 73.7% specificity), whereas aberrant mRNA expression of MUC1, MUC3A, MUC4, and MUC13 was distinctive for ulcerative colitis and of MUC3B for Crohn’s disease. Furthermore, expression of MUC3A, MUC3B, and MUC4 correlated with clinical disease activity (ie, Pediatric Ulcerative Colitis Activity Index and Pediatric Crohn’s Disease Activity Index), and of MUC1, MUC2, MUC4, and MUC13 with endoscopic colitis severity in ulcerative colitis patients. Conclusions Colonic mucin expression is disturbed in pediatric IBD patients and associates with disease activity and presentation, suggesting its use as molecular marker to aid in disease diagnosis and management.

Commissioned by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), we investigated how European physicians training in these fields are educated in nutrition. A survey on time spent in nutrition training, composition of multidisciplinary nutrition teams, and topics covered during training enrolled 50 participants. A median of 20% of training time was spent on nutrition training during fellowship. Fourteen (28%) had regular nutrition teaching. Thirty-four (68%) were part of a multidisciplinary nutrition team. Twelve (24%) used the ESPGHAN syllabus. Most frequent topics during nutrition training were diagnosis/investigation of failure to thrive, indications/contraindications for enteral feeds, and benefits/risks of enteral/parenteral nutrition. Twenty-seven (54%) had taken a formal nutrition course. Nutrition training in Europe varies and the ESPGHAN training syllabus is not yet implemented Europe-wide. ESPGHAN nutrition summer schools, and Web-based learning may provide appropriate training. We suggest that all patients necessitating nutritional care be treated by multidisciplinary nutrition teams.

A preterm boy, born at the gestational age of 26 weeks, developed a sepsis followed by obstructive cholestasis at the age of 4 weeks despite broad spectrum antibiotic and fluconazole treatment. Abdominal ultrasound showed masses of unknown origin in the gallbladder. An invasive fungal infection was diagnosed via serum (1,3)-beta-D-glucan. After initiation of the echinocandin caspofungin, inflammation and cholestasis parameters subsided quickly and the patient recovered. Accumulation of fungal balls in the gallbladder has been described as a cause of chronic obstructive cholestasis in immunocompromised adults, this is the first reported case in a preterm neonate.

AIM To identify factors other than active disease and anemia that contribute to fatigue in pediatric inflammatory bowel disease (IBD). METHODS We performed an electronic search in Medline and EMBASE from their inception to May 2017 using the search term "fatigue" or the related keywords "physical impairment" and "inflammatory bowel disease" with the filter "child" (age 0-18 years). Cross-sectional and case-control studies were included. We restricted our search to studies published in English. We used the PRISMA checklist and flow diagram. Duplicate articles were manually deleted in End Note. To identify further relevant studies, we checked the reference lists of the selected articles. RESULTS We identified 149 papers, of which 19 were retrieved for full text review. Eleven studies were subsequently excluded because fatigue was not evaluated as an outcome measure. Eight papers focused on the desired topic and were discussed in the final analysis. A lack of uniformity of outcome measures made the pooling of data impossible. In all but one study, questionnaires were used to evaluate fatigue. In the remaining study, an accelerometer was used to measure daily activities, sleeping time and their relationships with fatigue in a more quantifiable manner. Adolescents with IBD are significantly more fatigued than healthy controls. In addition to active disease, increased anxiety or depression and disturbed family relationships were frequently reported predictors of fatigue. Quantitative measurement of physical activity in patients with Crohn's disease showed a reduction in the number of steps per day, and patients with ulcerative colitis had a shorter duration of physical activity during the day. CONCLUSION Fatigue in pediatric IBD is related to a combination of biological, functional and behavioral factors, which should all be taken into account when managing fatigue.

Background: Irinotecan-induced gastro-intestinal side effects are well described in the literature. The pathophysiology and treatment of diarrhea, especially acute onset, is the most understood. Yet delayed onset cramps and management have not been sufficiently documented. Materials: A case report of a nine-year-old girl diagnosed with rhabdomyosarcoma who was treated with irinotecan in the relapse setting, is presented. A limited literature review was done based on the challenges experienced during the management of a patient with delayed onset irinotecaninduced cramps. The pathophysiology of delayed onset irinotecan induced cramps is based on cholinergic, inflammatory and enzymatic factors as well as neural damage. Treatment was based on the etiology described in the literature with a positive result. Conclusion: Delayed onset irinotecan related cramps are part of a multifactorial etiology that should be approached systematically, especially when first line treatment does not yield an adequate response.

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. Results: of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. the overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). in contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. Conclusion: the lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT., Styrian Children's Cancer Aid Foundation; Slovenian Research AgencySlovenian Research Agency - Slovenia [P3-0343]; Jonas S_oderquist Foundation; Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [217S847, 318S202]; Deutsche Forschungsgemeinschaft under Germany's Excellence StrategyGerman Research Foundation (DFG) [390939984, 39087428]; E-Rare program of the European Union by the Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [GR1617/14-1/iPAD]; Netzwerke Seltener Erkrankungen of the German Ministry of Education and Research [GAIN_ 01GM1910A]; Finnish Foundation for Pediatric Research and Pediatric Research Center, HUS Helsinki University Hospital; Graduate Research Training Scholarship of the Australian government; Hadassah Australia; ERN-RITA network [739543], M.G. Seidel and the Research Unit for Pediatric Hematology and Immunology are supported in part by the Styrian Children's Cancer Aid Foundation. M. Avbeli Stefanija was supported by the Slovenian Research Agency (grant P3-0343). H. Abolhassani was supported by the Jonas S_oderquist Foundation. S. Baris was supported by the Scientific and Technological Research Council of Turkey for the diagnosis of patients with LRBA deficiency (grants 217S847 and 318S202). B. Grimbacher receives support through the Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy (CIBSS-EXC-2189-Project ID 390939984 and RESIST-EXC 2155-Project ID 39087428); through the E-Rare program of the European Union, managed by the Deutsche Forschungsgemeinschaft (grant GR1617/14-1/iPAD); and through the Netzwerke Seltener Erkrankungen of the German Ministry of Education and Research (grant GAIN_ 01GM1910A). M.R.J. Sepp_anen was supported by the Finnish Foundation for Pediatric Research and Pediatric Research Center, HUS Helsinki University Hospital. I. Meyts is a member of the ERN-RITA network (project identification number 739543). B. Shadur is supported by a Graduate Research Training Scholarship of the Australian government and by Hadassah Australia.

ObjectiveTo evaluate quality of paediatric endoscopy training of Young members of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).MethodsAn online questionnaire designed by the Young ESPGHAN Committee was sent to 125 Young ESPGHAN members between February 2014 and September 2015. The questionnaire comprised 32 questions addressing some general information of the participants and the structure of their paediatric gastroenterology, hepatology and nutrition programmes; procedural volume and terminal ileal intubation (TII) rate; supervision, assessments, participation in endoscopy courses and simulator training; and satisfaction with endoscopy training and self-perceived competency.ResultsOf 68 participants, 48 (71%) were enrolled in an official training programme. All alumni (n=31) were trained in endoscopy. They completed a median of 200 oesophagogastroduodenoscopies (OGDs) and 75 ileocolonoscopies (ICs) with a TII rate of >90% in 43%. There is a significant difference in numbers of ICs between the TII rate groups >90%, 50%–90% and ConclusionsDespite reaching the suggested procedural endoscopy volumes, a rather low TII rate of >90% calls for end-of-training certifications based on the achievement of milestones of competency.

Item does not contain fulltext Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on more than 25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies, or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remain without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with an external review. They were implemented for novel entries and verification of existing data sets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance.

Mutations in STAT3 have recently been shown to cause autoimmune diseases through increased lymphoproliferation. We describe a novel Pro471Arg STAT3 mutation in a patient with multiple autoimmune diseases, causing hyperactivation of the Th17 pathway. We show that IL-17 production by primary T cells was enhanced and could not be further increased by IL-6, while IL-10 reduced Th17 cell numbers. Moreover, specific inhibition of STAT3 activation resulted in diminished IL-17 production. We show that the Pro471Arg STAT3 mutation yields both increased levels of IgA and IgG, probably due to high IL-21 levels. When remission was reached through medical intervention, IL-17 levels normalized and the clinical symptoms improved, supporting the idea that STAT3 gain-of-function mutations can cause hyperactivation of the Th17 pathway and thereby contribute to autoimmunity.

BACKGROUND & AIMS: Little is known about the pathophysiology of early onset forms of autoimmune enteropathy (AIE). AIE has been associated with mutations in FOXP3-a transcription factor that controls regulatory T-cell development and function. We analyzed the molecular basis of neonatal or early postnatal AIE using clinical, genetic, and functional immunological studies. METHODS: Gastroenterological and immunological features were analyzed in 9 boys and 2 girls with AIE that began within the first 5 months of life. FOXP3 and IL2RA were genotyped in peripheral blood monocytes. FOXP3 messenger RNA and protein expression were analyzed using reverse-transcription polymerase chain reaction, flow cytometry, and confocal immunofluorescence of CD4(+) T cells. Regulatory T-cell function (CD4(+)CD25(+)) was assayed in coculture systems. RESULTS: AIE associated with extraintestinal autoimmunity was severe and life-threatening; all patients required total parenteral nutrition. Regulatory T cells from 7 patients had altered function and FOXP3 mutations that resulted in lost or reduced FOXP3 protein expression; 2 infants had reduced regulatory T-cell activity and reduced levels of FOXP3 protein, although we did not detect mutations in FOXP3 coding region, poly-A site, or promoter region (called FOXP3-dependent AIE). Two patients had a normal number of regulatory T cells that expressed normal levels of FOXP3 protein and normal regulatory activity in in vitro coculture assays (called FOXP3-independent AIE). No mutations in IL2RA were found. CONCLUSIONS: Most cases of AIE are associated with alterations in regulatory T-cell function; some, but not all, cases have mutations that affect FOXP3 expression levels. Further studies are needed to identify mechanisms of AIE pathogenesis.

International audience; IL-15 drives chronic inflammation in several human diseases. We have recently shown that IL-15 inhibits the immunosuppressive effects of TGF-beta through blockage of the Smad3-signaling pathway. Data pointing to reciprocal interactions between TGF-beta and CD4(+) regulatory T cells led us to investigate the impact of IL-15 on the de novo generation and function of regulatory T cells in humans. Our data indicate that IL-15 does not counteract, but rather promotes the effect of TGF-beta on the de novo generation of regulatory T cells (Treg). Thus, in the presence of TGF-beta, IL-15 enhanced the acquisition of regulatory functions by CD4(+)CD25(-) T cells stimulated by anti-CD3 and anti-CD28 Abs. In contrast, IL-15 impaired the functions of Tregs by acting on effector CD4 and CD8 T cells. Accordingly, in the presence of IL-15, proliferation and IFN-gamma production by peripheral CD4 and CD8 T cells could not be efficiently inhibited by Tregs. IL-15-induced resistance of effector T cells to Tregs resulted from activation of the PI3K signaling pathway but did not involve the rescue of effector T cells from apoptosis. Altogether, these data point to the ambiguous role of EL-15 in the control of Treg functions. This dual role may be instrumental to mount rapid but transient proinflammatory immune responses against pathogens but may become deleterious in situations associated with protracted IL-15 over-expression. The Journal of Immunology, 2009, 182: 6763-6770.

Purpose of review Autoimmune enteropathy (AIE) is a distinct cause of severe and persistent inflammatory diarrhea in children. Recent research data allowed us to gain a first insight in the pathogenesis of AIE. On the basis of this data, we will discuss new aspects of AIE emphasizing new diagnostic and therapeutic possibilities. Recent findings With the discovery of disease-causing mutations in the FOXP3 gene in patients with AIE, a dramatic advance in the understanding of AIE was made. Subsequent studies indicated that FOXP3 is a key transcription factor indispensable for regulatory functions of T cells pointing to a critical role of regulatory T-cell homeostasis in the development of AIE. Abnormal FOXP3 expression results in defective regulatory functions of T cells, which in turn cause a systemic T-cell-mediated autoaggressive disorder, now called immune dysregulation, polyendocrinopathy autoimmune enteropathy X-linked syndrome. Upon systematic review, we describe different phenotypes of immune dysregulation polyendocrinopathy autoimmune enteropathy X-linked syndrome, as well as immune dysregulation polyendocrinopathy autoimmune enteropathy X-linked-like forms of AIE, which are FOXP3 independent. No genotype-phenotype correlation could be established so far. Summary On the basis of the profound immune dysregulation in AIE, new, most often T-cell-oriented treatment strategies were developed. The recent molecular advances in the understanding of AIE give a clear rational for the use of immunosuppression (combining steroids and tacrolimus or rapamycine) to stabilize AIE patients or to perform bone marrow transplantation in those who do not respond to immunomodulation.

Background & Aims: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX; OMIM 304930) syndrome is a congenital syndrome characterized by autoimmune enteropathy, endocrinopathy, dermatitis, and other autoimmune phenomena. In the present work, we aimed to uncover the molecular basis of a distinct form of IPEX syndrome presenting at the edge of autoimmunity and severe allergy. Methods: The FOXP3 gene was sequenced, FOXP3 messenger RNA (mRNA) was quantified by real-time polymerase chain reaction (PCR), and protein expression in peripheral blood lymphocytes was analyzed by flow cytometry after intracellular staining. In coculture experiments (CD4+CD25− and CD4+CD25+ cells), the functions of regulatory T cells were analyzed. Expression of interferon γ and interleukin 2 and 4 mRNA within the inflamed intestinal mucosa was quantified by real-time PCR. Results: Here, we describe a distinct familial form of IPEX syndrome that combines autoimmune and allergic manifestations including severe enteropathy, food allergies, atopic dermatitis, hyper-IgE, and eosinophilia. We have identified a 1388-base pair deletion (g.del−6247_−4859) of the FOXP3 gene encompassing a portion of an upstream noncoding exon (exon −1) and the adjacent intron (intron −1). This deletion impairs mRNA splicing, resulting in accumulation of unspliced pre-mRNA and alternatively spliced mRNA. This causes low FOXP3 mRNA levels and markedly decreased protein expression in peripheral blood lymphocytes of affected patients. Numbers of CD4+CD25+FOXP3+ regulatory T cells are extremely low, and the CD4+CD25+ T cells that are present exhibit little regulatory function. Conclusions: A new mutation within an upstream noncoding region of FOXP3 results in a variant of IPEX syndrome associating autoimmune and severe immunoallergic symptoms.