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Abstract: Introduction: Genetic polymorphism of thiopurine S-methyltransferase, the key enzyme in metabolism of thiopurines (azathioprine and 6-mercaptopurine) used in the treatment of inflammatory bowel disease, results in different enzyme activities. Decreased enzyme activity causes myelosuppression whereas abnormally high activity results in hepatotoxicity at standard thiopurine doses. Four allele variants (TMPT*2, TMPT*3A, TPMT*3B and TPMT*3C) account for decreased activity in more than 95% of cases. Aim: To evaluate the frequency of severe side effects, such as myelosuppression and hepatotoxicity, at standard or decreased azathioprine doses in children with inflammatory bowel disease who do not exhibit any of the four most common variant alleles. Method: Retrospective analysis of children with inflammatory bowel disease treated with azathioprine at a single tertiary referral center. Results: 51 patients were identified (44: Crohn’s disease, 7: ulcerative colitis; male ratio: 28/51; mean age at diagnosis: 12.4 years). Two patients discontinued azathioprine arbitrarily whereas in one patient it was stopped due to serious pancreatitis and in another one because of severe flu-like symptoms. None of the remaining 47 patients exhibited hepatotoxicity suggesting abnormally high thiopurine S-methyltransferase activity. Four patients (8.5%) had profound myelosuppression on less than 1 mg/kg/day azathioprine requiring discontinuation of the drug, and all of them showed complete bone marrow recovery subsequently. No myelosuppression occurred in the remaining 43 patients on 2.17 ± 0.31 mg/kg/day (mean ± SD) azathioprine treatment. Conclusions: Regular blood tests are necessary on thiopurine therapy despite normal thiopurine S-methyltransferase genotype because of the risk of myelosuppression. The four most common variant alleles were identified in routine genotyping only, therefore most likely rare variant allele(s) or polymorphism of other enzymes involved in thiopurine metabolism account for the aforementioned four cases with profound bone marrow suppression. Thiopurine metabolite monitoring is the key for individualized treatment when optimal dosing can be achieved with the least side effects. Orv Hetil. 2019; 160(5): 179–185.

At present, there is a significant amount of data related to biologics used in pediatric patients with Crohn's disease. This review characterizes the different biological drugs administered in this population.Biological therapy of CD, focusing on children, is summarized in this review. After mechanism of action and pharmacokinetics are described, mucosal healing on anti-TNF therapy, aspects of early therapy, long-term outcome and combination therapy are discussed. Moreover, loss of response and treatment optimization, as well as drug withdrawal are summarized. Subsequently, perianal disease and surgical aspects are discussed followed by safety issues. In addition, new drugs (vedolizumab, ustekinumab), cost-effectiveness and administration of biosimilars were also included.There are significant data to characterize biological drugs administered in pediatric patients with Crohn's disease. However, head-to-head comparative studies using different biologics are missing.

IntroductionInflammatory bowel diseases (IBD) are among the most common chronic illnesses diagnosed in childhood. Transition from paediatric to adult care is a crucial phase. The implementation of joint visits during the transition period in IBD is widely recommended, however, strong evidence supporting their benefit is still missing. In this trial, we aim to prove the superiority of joint visits compared with usual care in improving transition outcomes of adolescents with IBD.Methods and analysisThis is a randomised controlled two-arm multicentre trial. A minimum of 160 adolescents with IBD aged between 16.75 and 17 years will be recruited from Hungarian tertiary IBD centres. After randomisation, eligible subjects in the intervention arm attend a total of four joint visits with adult and paediatric gastroenterologist between the ages of 17 and 18. In the control arm, adolescents meet only the paediatric gastroenterologist, but there is a balanced consultation between the two gastroenterologist regarding the patient’s treatment plan. Patients in both groups receive the same training and education, the only determinative difference between the two arms is the presence of the adult gastroenterologist at the joint visits. Data will be collected at inclusion, at transfer and 12 months post-transfer. Primary outcome is the change in health-related quality of life measured with the IMPACT-III questionnaire at 1 year after transfer. Secondary outcomes include the number of patients not lost to follow-up, healthcare utilisation, disease activity, medication adherence, self-efficacy, transition readiness and patient’s satisfaction. To compare the results of the two patient groups, two-sample T-test and Mann-Whitney test will be applied.Ethics and disseminationThe Scientific and Research Ethics Committee of the Hungarian Medical Research Council approved this study (50457-2/2019/EKU). Findings will be disseminated at conferences and in medical journals.Trial registration numberNCT04290156.

Genetic polymorphism of thiopurine S-methyltransferase, the key enzyme in metabolism of thiopurines (azathioprine and 6-mercaptopurine) used in the treatment of inflammatory bowel disease, results in different enzyme activities. Decreased enzyme activity causes myelosuppression whereas abnormally high activity results in hepatotoxicity at standard thiopurine doses. Four allele variants (TMPT*2, TMPT*3A, TPMT*3B and TPMT*3C) account for decreased activity in more than 95% of cases.To evaluate the frequency of severe side effects, such as myelosuppression and hepatotoxicity, at standard or decreased azathioprine doses in children with inflammatory bowel disease who do not exhibit any of the four most common variant alleles.Retrospective analysis of children with inflammatory bowel disease treated with azathioprine at a single tertiary referral center.51 patients were identified (44: Crohn's disease, 7: ulcerative colitis; male ratio: 28/51; mean age at diagnosis: 12.4 years). Two patients discontinued azathioprine arbitrarily whereas in one patient it was stopped due to serious pancreatitis and in another one because of severe flu-like symptoms. None of the remaining 47 patients exhibited hepatotoxicity suggesting abnormally high thiopurine S-methyltransferase activity. Four patients (8.5%) had profound myelosuppression on less than 1 mg/kg/day azathioprine requiring discontinuation of the drug, and all of them showed complete bone marrow recovery subsequently. No myelosuppression occurred in the remaining 43 patients on 2.17 ± 0.31 mg/kg/day (mean ± SD) azathioprine treatment.Regular blood tests are necessary on thiopurine therapy despite normal thiopurine S-methyltransferase genotype because of the risk of myelosuppression. The four most common variant alleles were identified in routine genotyping only, therefore most likely rare variant allele(s) or polymorphism of other enzymes involved in thiopurine metabolism account for the aforementioned four cases with profound bone marrow suppression. Thiopurine metabolite monitoring is the key for individualized treatment when optimal dosing can be achieved with the least side effects. Orv Hetil. 2019; 160(5): 179-185.Absztrakt: Bevezetés: A gyulladásos bélbetegség kezelésében alkalmazott tiopurinok (azatioprin és 6-merkaptopurin) metabolizmusában kulcsszerepet játszó tiopurin-S-metiltranszferáz enzim genetikai polimorfizmusa változó enzimaktivitást eredményez. A csökkent enzimaktivitás mieloszuppressziót, kifejezetten magas pedig hepatotoxicitást okoz standard tiopurindózis mellett. Négy allélvariáns (TMPT*2, TMPT*3A, TPMT*3B és TPMT*3C) felelős több mint 95%-ban a csökkent aktivitásért. Célkitűzés: A standard vagy csökkentett azatioprindózis ellenére is fellépő súlyos mellékhatások – úgymint csontvelő-depresszió, illetve hepatotoxicitás – gyakoriságának vizsgálata a fenti 4 variáns alléllal nem rendelkező gyulladásos bélbeteg gyermekeknél. Módszer: Retrospektív vizsgálat a Pécsi Tudományegyetem Gyermekgyógyászati Klinikáján gondozott, azatioprinkezelésben részesülő gyulladásos bélbeteg gyermekeknél. Eredmények: A fenti kritériumoknak 51 beteg felelt meg (44: Crohn-betegség, 7: colitis ulcerosa; a fiúk aránya: 28/51; átlagéletkor a diagnózis idején: 12,4 év). Az azatioprinkezelést két beteg önkényesen elhagyta, egy betegnél súlyos pancreatitis, egy másiknál pedig kifejezett influenzaszerű tünetek miatt állítottuk le. A fennmaradó 47 beteg egyikénél sem jelentkezett májtoxicitás, mely közvetve kifejezetten magas tiopurin-S-metiltranszferáz-aktivitásra utal. Négy betegnél (8,5%) 1 mg/kg/nap-nál alacsonyabb azatioprindózis esetén is fennálló mieloszuppresszió miatt a kezelést le kellett állítani, s ezt követően maradéktalan volt a csontvelői regeneráció. A fennmaradó 43 betegnél 2,17 ± 0,31 mg/kg/nap (átlag ± SD) dózisú azatioprinkezelés mellett csontvelő-depressziót nem észleltünk. Következtetés: Tiopurinkezelés esetén még normális tiopurin-S-metiltranszferáz-genotípus mellett is mindenképpen szükséges a rendszeres laborkontroll a mieloszuppresszió kockázata miatt. Mivel a genotípus meghatározása a 4 leggyakoribb allélt érintette, ritkább variáns(ok) vagy egyéb enzim polimorfizmusa is állhat a fenti 4 csontvelő-depressziós eset hátterében. A tiopurinmetabolitok monitorizálása elengedhetetlen segítséget nyújt az egyénre szabott kezelésben, azaz az elérhető legkevesebb mellékhatás mellett az optimális dózis beállításában. Orv Hetil. 2019; 160(5): 179–185.

Tracheal agenesis – failure of trachea development - is an extremely rare and severe congenital disorder involving the respiratory system and in most cases it is associated with other abnormalities. Three anatomic types of tracheal agenesis were described by Floyd. Antenatal diagnosis is difficult, especially if it is combined with a tracheo-oesophageal fistula. We report a postnatally diagnosed case of a female newborn with Type II tracheal agenesis. Polyhydramnios and right upper limb anomaly were diagnosed prenatally. Only typical postnatal clinical signs, such as severe asphyxia with strong respiratory efforts, no audible cry, failed endotracheal intubation and no palpable tracheal tissue on the neck aroused suspicion of tracheal agenesis. Despite the few published cases when antenatal diagnosis of tracheal agenesis and series of heroic postnatal surgical interventions resulted in few years’ survival, tracheal agenesis is still considered as a lethal condition. Possibilities of antenatal diagnosis, postnatal management and therapeutic options are discussed.

Purpose To evaluate the effect of our current transition process on clinical outcomes in adolescent patients with inflammatory bowel diseases (IBD). Design and methods Two groups of patients with IBD diagnosed in pediatric care were compared retrospectively: Group A patients did not attend the transition process, while Group B patients entered the planned transition service. Outcomes at 1-year after transfer to adult care were evaluated. Results Forty-five patients with IBD diagnosed under the age of 18 years were identified of whom 35 had Crohn's disease and 10 had ulcerative colitis. Twenty-four patients were in Group A (without transition), and 21 patients in Group B (with at least one planned transition visit). Mean age at diagnosis was 15.1 ± 2.2 and 13.7 ± 3.0 years (p = 0.086), respectively. There were no significant differences in disease duration before transfer, Montreal classification at diagnosis, body mass index, anti-TNF therapy usage, and disease status at transfer between the two groups. A significantly higher number of Group B patients were in remission at 12 months after transfer when compared to patients in Group A (11 vs. 18, respectively, p = 0.037). There was a significant difference between groups regarding the number of scheduled visits within the examined period (9 vs. 16, p = 0.011, respectively). Conclusions Planned transition visits resulted in higher disease remission rate at 1-year follow-up after transfer from pediatric to adult health care system in adolescent patients with IBD. Practice implication Well-established transition programs in IBD are needed.

BACKGROUND Laboratory markers are essential tools in the follow-up of patients with Crohn's disease (CD). Our aim was to investigate urinary concentrations of orosomucoid in relation to the inflammatory activity of CD and to compare it with clinical indices and conventional laboratory parameters. MATERIALS AND METHODS Blood and urine samples of 86 patients (55 adults and 31 children) with CD and 68 healthy individuals (38 adults and 30 children) as controls were analysed. Patients were categorized according to their clinical scores (Harvey-Bradshaw Index [HBI] or Pediatric Crohn's Disease Activity Index [PCDAI]). Urinary orosomucoid (u-ORM) was determined by automated immune turbidimetric assay, and values were referred to urinary creatinine (u-ORM/u-CREAT, mg/mmol). RESULTS U-ORM/u-CREAT values were seven times higher in children with active CD (0.50 vs 0.07 mg/mmol, P

OBJECTIVE Fat malabsorption can occur in celiac disease (CD) owing to villus atrophy and inflammation of small intestinal mucosa. Abnormal fatty acid (FA) status of intestinal mucosa in children with CD was reported earlier. Previously we found significantly reduced availability of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) in children and young adults with type 1 diabetes mellitus (DM). The aim of this study was to investigate FAs in plasma lipid classes in children with newly diagnosed CD with or without preexisting DM. METHODS FA composition of plasma samples of children with untreated CD only (n = 20) and with preexisting DM (CDDM, n = 8) were compared with those of healthy controls (n = 21). Detailed analysis of phospholipid, triacylglycerol, and sterol ester FAs was performed by high-resolution capillary gas-liquid chromatography. RESULTS Significantly decreased docosapentaenoic (C22:5n-3), docosahexaenoic (C22:6n-3), n-3 polyunsaturated fatty acids (n-3 PUFA), and n-3 LCPUFA values were found in CDDM group compared with controls and patients with CD. When compared with healthy controls, no significant difference was found in plasma FAs of children with newly diagnosed CD only. CONCLUSIONS Children with CDDM showed marked signs of reduced availability of n-3 PUFA and n-3 LCPUFA in circulating lipids. Although different tissues express membrane FAs differently, our present study suggests that CD on its own does not necessarily lead to detectable disturbances of essential FA metabolism in plasma and supports the concept that DM has significant impact on plasma FA composition in children.

OBJECTIVES The aim of the study was to evaluate the incidence, baseline disease characteristics, and disease location based on the Paris classification in pediatric inflammatory bowel disease (IBD) in the Hungarian nationwide inception cohort. In addition, 1-year follow-up with therapy was analyzed. METHODS From January 1, 2007 to December 31, 2009, newly diagnosed pediatric patients with IBD were prospectively registered. Twenty-seven pediatric gastroenterology centers participated in the data collection ensuring the data from the whole country. Newly diagnosed patients with IBD younger than 18 years were reported. Disease location was classified according to the Paris classification. RESULTS A total of 420 patients were identified. The incidence rate of pediatric IBD was 7.48/10⁵ (95% confidence interval [CI] 6.34/10⁵-8.83/10⁵). The incidence for Crohn disease (CD) was 4.72/10⁵ (95% CI 3.82-5.79), for ulcerative colitis (UC) 2.32/10⁵ (95% CI 1.71-3.09), and for IBD-unclassified 0.45/10⁵ (95% CI 0.22-0.84). Most common location in CD was L3 (58.7%); typical upper gastrointestinal abnormalities (ulcer, erosion and aphthous lesion) were observed in 29.9%. Extensive colitis in patients with UC (E4, proximal to hepatic flexure) was the most common disease phenotype (57%), whereas only 5% of children had proctitis. A total of 18.6% of patients had ever severe disease (S1). Frequency of azathioprine administration at diagnosis was 29.5% in patients with CD, and this rate increased to 54.6% (130/238) at 1-year follow-up. In UC, only 3.3% received azathioprine initially, and this rate elevated to 22.5% (25/111). Use of corticosteroid decreased from 50% to 15.3% in patients with UC. Rate of bowel resection in patients with CD during the first year of follow-up was 5%. CONCLUSIONS The incidence of pediatric IBD in Hungary was among the higher range reported. This is the first large, nationwide incident cohort analyzed according to the Paris classification, which is a useful tool to determine the characteristic pediatric CD phenotype.

Background: In contrast with other malformations, congenital anomalies of the gastrointestinal tract have been scarcely investigated. Methods: The prevalence of gastrointestinal malformations with special reference to associated disorders and intrauterine growth was retrospectively analyzed in the newborn infants admitted to the Neonatal Intensive Care Unit of the Department of Pediatrics, University of Pecs, Hungary, in the 14-year period between 1987 and 2000. Results: Of 4,241 neonates with gastrointestinal malformations, 241 (5.68%) had a total of 304 malformations (excluding Hirschsprung disease). In 133 patients, the gastrointestinal anomalies were observed as one of multiple malformations; a specific syndrome or association was diagnosed in 36 cases. Skeletal disorders were the most frequently associated anomalies. Intrauterine growth retardation was found in a large number of patients with both isolated and multiple gastrointestinal malformations (38.9% and 30.8%, respectively). Conclusions: Gastrointestinal malformations often are complicated by skeletal anomalies and intrauterine growth retardation. The association among these disorders requires further investigation. However, from a practical point of view, this association should be considered in treating affected patients.