Prediction Models for Celiac Disease Development in Children From High-Risk Families: Data From the PreventCD Cohort.

BACKGROUND & AIMS: Screening for celiac disease (CD) is recommended in children with affected first-degree relatives (FDR). However, the frequency of screening and at what age remain unknown. The aims of this study were to detect variables influencing the risk of CD development and develop and validate clinical prediction models to provide individualized screening advice. METHODS: We analyzed prospective data from the 10 years of follow-up of the PreventCD-birth cohort involving 944 genetically predisposed children with CD-FDR. Variables significantly influencing the CD risk were combined to determine a risk score. Landmark analyses were performed at different ages. Prediction models were created using multivariable Cox proportional hazards regression analyses, backward elimination, and Harrell's c-index for discrimination. Validation was done using data from the independent NeoCel cohort. RESULTS: In March 2019, the median follow-up was 8.3 years (22 days-12.0 years); 135/944 children developed CD (mean age, 4.3 years [range, 1.1-11.4]). CD developed significantly more often in girls (P = .005) and in Human Leukocyte Antigen (HLA)-DQ2 homozygous individuals (8-year cumulative incidence rate of 35.4% vs maximum of the other HLA-risk groups 18.2% [P < .001]). The effect of homozygosity DR3-DQ2/DR7-DQ2 on CD development was only present in girls (interaction P = .04). The prediction models showed good fit in the validation cohort (Cox regression 0.81 [0.54]). To calculate a personalized risk of CD development and provide screening advice, we designed the Prediction application https://hputter.shinyapps.io/preventcd/. CONCLUSION: Children with CD-FDR develop CD early in life, and their risk depends on gender, age and HLA-DQ, which are all factors that are important for sound screening advice. These children should be screened early in life, including HLA-DQ2/8-typing, and if genetically predisposed to CD, they should get further personalized screening advice using our Prediction application. TRIAL REGISTRATION NUMBER: ISRCTN74582487 (https://www.isrctn.com/search?q=ISRCTN74582487).

Management of Helicobacter pylori infection in paediatric patients in Europe: results from the EuroPedHp Registry.

PURPOSE: The EuroPedHp-registry aims to monitor guideline-conform management, antibiotic resistance, and eradication success of 2-week triple therapy tailored to antibiotic susceptibility (TTT) in Helicobacter pylori-infected children. METHODS: From 2017 to 2020, 30 centres from 17 European countries reported anonymized demographic, clinical, antibiotic susceptibility, treatment, and follow-up data. Multivariable logistic regression identified factors associated with treatment failure. RESULTS: Of 1605 patients, 873 had follow-up data (53.2% female, median age 13.0 years, 7.5% with ulcer), thereof 741 (85%) treatment naïve (group A) and 132 (15%) after failed therapy (group B). Resistance to metronidazole was present in 21% (A: 17.7%, B: 40.2%), clarithromycin in 28.8% (A: 25%, B: 51.4%), and both in 7.1% (A: 3.8%, B: 26.5%). The majority received 2-week tailored triple therapy combining proton pump inhibitor (PPI), amoxicillin with clarithromycin (PAC) or metronidazole (PAM). Dosing was lower than recommended for PPI (A: 49%, B: 41%) and amoxicillin (A: 6%, B: 56%). In treatment naïve patients, eradication reached 90% (n = 503, 95% CI 87-93%) and 93% in compliant children (n = 447, 95% CI 90-95%). Tailored triple therapy cured 59% patients after failed therapy (n = 69, 95% CI 48-71%). Treatment failure was associated with PAM in single clarithromycin resistance (OR = 2.47, 95% CI 1.10-5.53), with PAC in single metronidazole resistance (OR = 3.44, 95% CI 1.47-8.08), and with low compliance (OR = 5.89, 95% CI 2.49-13.95). CONCLUSIONS: Guideline-conform 2-weeks therapy with PPI, amoxicillin, clarithromycin or metronidazole tailored to antibiotic susceptibility achieves primary eradication of ≥ 90%. Higher failure rates in single-resistant strains despite tailored treatment indicate missed resistance by sampling error.

Changes in Non-Deamidated versus Deamidated Epitope Targeting and Disease Prediction during the Antibody Response to Gliadin and Transglutaminase of Infants at Risk for Celiac Disease.

Celiac disease (CeD) is a conditional autoimmune disorder with T cell-mediated immune response to gluten coupled with antibody production to gliadin and the self-protein tissue transglutaminase (TG2). TG2 contributes to the CeD pathomechanism by deamidating gliadin, thereby generating more immunogenic peptides. Anti-gliadin antibodies may appear before the autoantibody production. The scope of this study was to dissect these early antibody responses by investigating serum samples collected during the PreventCD prospective double-blind study, where infants with high CeD risk were randomized to 200 mg daily gluten intake or placebo from 4 to 6 months of age, followed by frequent blood testing on regular gluten consumption in both groups. After primary gluten intake, children with or without later CeD produced IgA and IgG antibodies which preferentially recognized non-deamidated gliadin peptides. At CeD development with anti-TG2 seroconversion, there was a significant increase in the antibody reaction toward deamidated gliadin peptides (DGP), with maturation in the binding strength for the PEQPFP gamma-gliadin core peptide. The earliest produced autoantibodies targeted TG2's celiac epitope 2. Our results reveal a qualitative change in the gliadin-directed humoral immune response at the time when anti-TG2 antibodies appear, but anti-DGP antibodies in the absence of anti-TG2 antibodies are not disease-predictive.

Gamma-gliadin specific celiac disease antibodies recognize p31-43 and p57-68 alpha gliadin peptides in deamidation related manner as a result of cross-reaction.

Celiac disease (CeD) is a T-cell-dependent enteropathy with autoimmune features where tissue transglutaminase (TG2)-mediated posttranslational modification of gliadin peptides has a decisive role in the pathomechanism. The humoral immune response is reported to target mainly TG2-deamidated γ-gliadin peptides. However, α-gliadin peptides, like p57-68, playing a crucial role in the T-cell response, and p31-43, a major trigger of innate responses, also contain B-cell gliadin epitopes and γ-gliadin like motifs. We aimed to identify if there are anti-gliadin-specific antibodies in CeD patients targeting the p31-43 and p57-68 peptides and to examine whether deamidation of these peptides could increase their antigenicity. We explored TG2-mediated deamidation of the p31-43 and p57-68 peptides, and investigated serum antibody reactivity toward the native and deamidated α and γ-gliadin peptides in children with confirmed CeD and in prospectively followed infants at increased risk for developing CeD. We affinity-purified antibody populations utilizing different single peptide gliadin antigens and tested their binding preferences for cross-reactivity in real-time interaction assays based on bio-layer interferometry. Our results demonstrate that there is serum reactivity toward p31-43 and p57-68 peptides, which is due to cross-reactive γ-gliadin specific antibodies. These γ-gliadin specific antibodies represent the first appearing antibody population in infancy and they dominate the serum reactivity of CeD patients even later on and without preference for deamidation. However, for the homologous epitope sequences in α-gliadins shorter than the core QPEQPFP heptapeptide, deamidation facilitates antibody recognition. These findings reveal the presence of cross-reactive antibodies in CeD patients recognizing the disease-relevant α-gliadins.

Clinical Presentation in Children With Coeliac Disease in Central Europe.

OBJECTIVES: During the past decades, there has been a shift in the clinical presentation of coeliac disease (CD) to nonclassical, oligosymptomatic, and asymptomatic forms. We assessed clinical presentation of CD in children and adolescents in Central Europe. METHODS: Paediatric gastroenterologists in 5 countries retrospectively reported data of their patients diagnosed with CD. Clinical presentation was analyzed and the differences among very young (<3 years) and older children and adolescents were studied. RESULTS: Data from 653 children and adolescents (median age 7 years 2 months; 63.9% girls) from Croatia, Germany, Hungary, Italy, and Slovenia were available for the analysis. One fifth (N = 134) of all children were asymptomatic. In symptomatic children, the most common leading symptom was abdominal pain (33.3%), followed by growth retardation (13.7%) and diarrhoea (13.3%). The majority of symptomatic children (47.6%; N = 247) were polysymptomatic. Abdominal pain was the most common symptom in polysymptomatic (66.4%) as well as in monosymptomatic children (29.7%). Comparing clinical presentation of CD in very young children (younger than 3 years) with older children (3 years or older), we found that symptoms and signs of malabsorption were significantly more common in younger (P < 0.001), whereas abdominal pain and asymptomatic presentation were more common in older children and adolescents (both P < 0.001). CONCLUSION: In children with CD, abdominal pain has become the most common symptom. However, in younger children, symptoms of malabsorption are still seen frequently. This raises a question about the underlying mechanism of observed change in clinical presentation in favour of nonclassical presentation and asymptomatic disease at certain age.

The Knowledge About Celiac Disease Among Healthcare Professionals and Patients in Central Europe.

OBJECTIVES: Celiac disease (CD) remains undiagnosed for a long time in many adult and pediatric patients. We assessed the knowledge about CD among healthcare professionals (HCPs) and CD patients in Central Europe (CE). METHODS: HCPs and CD patients from 5 CE countries were asked to complete the web-based questionnaire about CD. The questions were divided into subsections on epidemiology, clinical presentation, diagnostics, treatment, and follow-up. Achieved scores of different specialists managing patients with CD were compared and regional differences in patients' knowledge were analyzed. RESULTS: Questionnaire was completed by 1381 HCPs and 2262 CD patients or their caregivers from Croatia, Hungary, Germany, Italy, and Slovenia. Mean score achieved by HCPs was 50.9%, and by CD patients 56.4%. Pediatric gastroenterologists scored the highest (69.4%; P < 0.001). There were significant differences in knowledge of patients from different CE regions with German participants scoring the highest (58.3%). Members of CD societies scored higher compared with nonmembers (mean score 58% vs 53.2%; P < 0.001) and patients diagnosed less than 5 years ago scored higher compared with those diagnosed more than 10 years ago (mean score 57.3% vs 54.6%; P < 0.001). CONCLUSIONS: The knowledge about CD among HCPs and CD patients is not satisfactory. Further awareness-raising and learning activities are needed to improve HCPs' knowledge and to minimize the number of unrecognized patients and unnecessary diagnostic delays. Patients should be better informed about their disease to reach higher compliance with the gluten-free diet.

European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020.

OBJECTIVES: The ESPGHAN 2012 coeliac disease (CD) diagnostic guidelines aimed to guide physicians in accurately diagnosing CD and permit omission of duodenal biopsies in selected cases. Here, an updated and expanded evidence-based guideline is presented. METHODS: Literature databases and other sources of information were searched for studies that could inform on 10 formulated questions on symptoms, serology, HLA genetics, and histopathology. Eligible articles were assessed using QUADAS2. GRADE provided a basis for statements and recommendations. RESULTS: Various symptoms are suggested for case finding, with limited contribution to diagnostic accuracy. If CD is suspected, measurement of total serum IgA and IgA-antibodies against transglutaminase 2 (TGA-IgA) is superior to other combinations. We recommend against deamidated gliadin peptide antibodies (DGP-IgG/IgA) for initial testing. Only if total IgA is low/undetectable, an IgG-based test is indicated. Patients with positive results should be referred to a paediatric gastroenterologist/specialist. If TGA-IgA is ≥10 times the upper limit of normal (10× ULN) and the family agrees, the no-biopsy diagnosis may be applied, provided endomysial antibodies (EMA-IgA) will test positive in a second blood sample. HLA DQ2-/DQ8 determination and symptoms are not obligatory criteria. In children with positive TGA-IgA <10× ULN at least 4 biopsies from the distal duodenum and at least 1 from the bulb should be taken. Discordant results between TGA-IgA and histopathology may require re-evaluation of biopsies. Patients with no/mild histological changes (Marsh 0/I) but confirmed autoimmunity (TGA-IgA/EMA-IgA+) should be followed closely. CONCLUSIONS: CD diagnosis can be accurately established with or without duodenal biopsies if given recommendations are followed.

Helicobacter pylori Infection in Pediatric Patients Living in Europe: Results of the EuroPedHP Registry 2013 to 2016.

OBJECTIVES: The aim of the study was to assess clinical presentation, endoscopic findings, antibiotic susceptibility and treatment success of Helicobacter pylori (H. pylori) infected pediatric patients. METHODS: Between 2013 and 2016, 23 pediatric hospitals from 17 countries prospectively submitted data on consecutive H. pylori-infected (culture positive) patients to the EuroPedHP-Registry. RESULTS: Of 1333 patients recruited (55.1% girls, median age 12.6 years), 1168 (87.6%) were therapy naïve (group A) and 165 (12.4%) had failed treatment (group B). Patients resided in North/Western (29.6%), Southern (34.1%) and Eastern Europe (23.0%), or Israel/Turkey (13.4%). Main indications for endoscopy were abdominal pain or dyspepsia (81.2%, 1078/1328). Antral nodularity was reported in 77.8% (1031/1326) of patients, gastric or duodenal ulcers and erosions in 5.1% and 12.8%, respectively. Primary resistance to clarithromycin (CLA) and metronidazole (MET) occurred in 25% and 21%, respectively, and increased after failed therapy. Bacterial strains were fully susceptible in 60.5% of group A, but in only 27.4% of group B. Primary CLA resistance was higher in Southern and Eastern Europe (adjusted odds ratio [ORadj] = 3.44, 95% confidence interval [CI] 2.22-5.32, P < 0.001 and 2.62, 95% CI: 1.63-4.22, P < 0.001, respectively) compared with Northern/Western Europe. Children born outside Europe showed higher primary MET resistance (ORadj = 3.81, 95% CI: 2.25-6.45, P < 0.001). Treatment success in group A reached only 79.8% (568/712) with 7 to 14 days triple therapy tailored to antibiotic susceptibility. CONCLUSIONS: Peptic ulcers are rare in dyspeptic H. pylori-infected children. Primary resistance to CLA and MET is markedly dependent on geographical regions of birth and residence. The ongoing survey will show whether implementation of the updated ESPGHAN/NASPGHAN guidelines will improve the eradication success.

Diagnostic Delays in Children With Coeliac Disease in the Central European Region.

OBJECTIVES: Coeliac disease (CD) is a systemic autoimmune disorder affecting about 1% of the population. Many patients remain undiagnosed or are diagnosed with substantial delay. We assessed diagnostic delays in symptomatic CD children in Central Europe (CE). METHODS: Paediatric gastroenterologists in 5 CE countries retrospectively reported data of their patients diagnosed in 2016. Age at first CD-related symptom(s), first visit to paediatric gastroenterologist and confirmed diagnosis were used to determine diagnostic delays. RESULTS: Data from 393 children (65% girls, median age 7 years, range 7 months to 18.5 years) from Croatia, Hungary, Germany, Italy, and Slovenia were analysed. Median duration from first symptom(s) to visit to paediatric gastroenterologist was 5 months (range 0-10 years; preschool 4 months, school-aged 5 months), and further duration until final diagnosis was 1 month (range 0-5 years) with significant regional differences (P < 0.001). Median diagnostic delay was 6 months (range 0-10 years; preschool 5 months, school-aged 7 months). Type of clinical presentation had little, however, significant effect on delays. Reduced body mass in delays longer than 3 years compared with delays shorter than 1 year was found (z score -0.93 vs -0.39, P < 0.05). CONCLUSIONS: Time from first symptoms to CD diagnosis in children in 5 CE countries is slightly shorter compared with few other small paediatric studies, and significantly shorter than reported for adults. Nevertheless, delays of more than 3 years in 6.6% of children are worrisome. Raising awareness about the variable symptoms and implementation of reliable diagnostic tools will further reduce diagnostic delays.

Accuracy in Diagnosis of Celiac Disease Without Biopsies in Clinical Practice.

BACKGROUND & AIMS: The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. METHODS: We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. RESULTS: Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61-99.99); the PPV was 100.00 (95% CI, 98.68-100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67-99.96) to 100.00 (95% CI, 99.23-100.00). CONCLUSIONS: Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

Hyperadiponectinemia During Infliximab Induction Therapy in Pediatric Crohn Disease.

OBJECTIVES: The inflammatory process in Crohn disease (CD) involves the visceral fat, characterized by adipocyte hyperplasia and altered adipose tissue and serum concentrations of tumor necrosis factor (TNF), leptin, adiponectin and resistin. We investigated the effect of anti-TNF therapy with infliximab (IFX) on serum adipokine levels in pediatric CD. METHODS: Serum concentrations of resistin (ng/mL), leptin (ng/mL), and total adiponectin (µg/mL) were assessed by enzyme-linked immunosorbent assays (ELISA) in 18 pediatric CD patients (mean age 15.0 ±â€Š1.5 years) before first, second, and fourth IFX infusion (weeks 0, 2, and 14) and compared with baseline values from sex- and BMI-matched healthy controls (HC, mean age 13.4 ±â€Š1.6 years). RESULTS: At baseline, CD patients (mean age 15.0 ±â€Š1.5 years, 10 of 18 boys) compared with HC (13.4 ±â€Š1.6 years, 7 of 15 boys) had higher resistin levels (median 14.7 ng/mL, range 5.1-50.5 vs 7.3 ng/mL, 0.5-14.5); P = 0.0002). At weeks 2 and 14, resistin decreased to 6.9 ng/mL (2.9-16.8) (P < 0.0001) and 9.2 ng/mL (4.1-20.6; P = 0.0011), respectively. Leptin and adiponectin were comparable between patients and HC at baseline. Leptin increased in girls from 9.5 ng/mL (4.0-30.1) to 16.0 ng/mL (7.9-35.2; P = 0.0156) and 17.2 ng/mL (10.8- 26.8; P = 0.1953) at weeks 0, 2, and 14 respectively; with a trend in boys from 2 (0.6-12.9) to 2.8 (1.7-8.6; P = 0.0840) and 3.3 (1.3-4.6; P = 0.1309). Adiponectin peaked initially from 7.8 µg/mL (4.6-11.9) at week 0 to 9.2 µg/mL (4.1-20.7; P = 0.0005) at week 2 and thereafter fell to 6.5 µg/mL (3.0-12.7; P = 0.0182) at week 14. CONCLUSIONS: TNF blockade is associated with changes in circulating adipokines. The marked early increase of the potent anti-inflammatory adiponectin may contribute to the rapid response to IFX in CD.

Incidence and Risk Factors for Perianal Disease in Pediatric Crohn Disease Patients Followed in CEDATA-GPGE Registry.

OBJECTIVES: Perianal disease (PD) with fistula and/or abscess formation is a severe complication in Crohn disease (CD). We examined prevalence, incidence, and risk factors for PD development in a pediatric CD cohort. METHODS: Patients with CD from the prospective, multicenter registry for inflammatory bowel disease from Germany and Austria (CEDATA-GPGE) were included if diagnosed at the age of 18 years or younger, registered within 3 months after diagnosis, and having at least 2 follow-up visits within the first year of registration. We examined potential risk factors for PD with Kaplan-Meier analysis and a final Cox model considering sex, family history of inflammatory bowel disease, extraintestinal manifestations, disease location, and induction therapy (corticosteroids or nutritional therapy). RESULTS: Of 2406 patients with CD, 742 fulfilled inclusion criteria (59% boys, mean age at diagnosis 12.4 ±â€Š3.4 years). PD was present at diagnosis in 41 patients (5.5%; 80.9% boys), whereas 32 patients (4.3%, 81.3% male) developed PD during follow-up (mean 2.0 ±â€Š1.6 years). The cumulative incidence of PD at 12 and 36 months after diagnosis was 3.5% and 7.5%, respectively. Potential risk factors for PD development during follow-up were male sex (hazard ratio = 3.2, [95%; confidence interval 1.2-7.8]) and induction therapy with corticosteroids (hazard ratio = 2.5 [1.1-5.5]). Diagnostic evaluation at PD diagnosis was incomplete in 40% of affected subjects. PD resolved within 1 year in 50% of cases. CONCLUSIONS: Approximately 10% of CD patients in our cohort suffered from PD within the first 3 years of their disease. Male sex and initial corticosteroid therapy were associated with an increased risk to develop PD after diagnosis.

Randomized feeding intervention in infants at high risk for celiac disease.

BACKGROUND: A window of opportunity has been suggested for reducing the risk of celiac disease by introducing gluten to infants at 4 to 6 months of age. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled dietary-intervention study involving 944 children who were positive for HLA-DQ2 or HLA-DQ8 and had at least one first-degree relative with celiac disease. From 16 to 24 weeks of age, 475 participants received 100 mg of immunologically active gluten daily, and 469 received placebo. Anti-transglutaminase type 2 and antigliadin antibodies were periodically measured. The primary outcome was the frequency of biopsy-confirmed celiac disease at 3 years of age. RESULTS: Celiac disease was confirmed by means of biopsies in 77 children. To avoid underestimation of the frequency of celiac disease, 3 additional children who received a diagnosis of celiac disease according to the 2012 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition diagnostic criteria (without having undergone biopsies) were included in the analyses (80 children; median age, 2.8 years; 59% were girls). The cumulative incidence of celiac disease among patients 3 years of age was 5.2% (95% confidence interval [CI], 3.6 to 6.8), with similar rates in the gluten group and the placebo group (5.9% [95% CI, 3.7 to 8.1] and 4.5% [95% CI, 2.5 to 6.5], respectively; hazard ratio in the gluten group, 1.23; 95% CI, 0.79 to 1.91). Rates of elevated levels of anti-transglutaminase type 2 and antigliadin antibodies were also similar in the two study groups (7.0% [95% CI, 4.7 to 9.4] in the gluten group and 5.7% [95% CI, 3.5 to 7.9] in the placebo group; hazard ratio, 1.14; 95% CI, 0.76 to 1.73). Breast-feeding, regardless of whether it was exclusive or whether it was ongoing during gluten introduction, did not significantly influence the development of celiac disease or the effect of the intervention. CONCLUSIONS: As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children. (Funded by the European Commission and others; PreventCD Current Controlled Trials number, ISRCTN74582487.).

Investigating the early metabolic fingerprint of celiac disease - a prospective approach.

OBJECTIVES AND STUDY: In the development of Celiac Disease (CD) both genetic and environmental factors play a crucial role. The Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 loci are strongly related to the disease and are necessary but not sufficient for the development of CD. Therefore, increasing interest lies in examining the mechanisms of CD onset from the early beginning. Differences in serum and urine metabolic profiles between healthy individuals and CD patients have been reported previously. We aimed to investigate if the metabolic pathways were already altered in young, 4 month old infants, preceding the CD diagnosis. METHODS: Serum samples were available for 230 four month old infants of the PreventCD project, a multicenter, randomized, double-blind, dietary intervention study. All children were positive for HLA-DQ2 and/or HLA-DQ8 and had at least one first-degree relative diagnosed with CD. Amino acids were quantified after derivatization with liquid chromatography - tandem mass spectrometry (MS/MS) and polar lipid concentrations (acylcarnitines, lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins) were determined with direct infusion MS/MS. We investigated the association of the metabolic profile with (1) the development of CD up to the age of 8 years (yes/no), (2) with HLA-risk groups, (3) with the age at CD diagnosis, using linear mixed models and cox proportional hazards models. Gender, intervention group, and age at blood withdrawal were included as potential confounder. RESULTS: By the end of 2014, thirty-three out of the 230 children (14%) were diagnosed with CD according to the ESPGHAN criteria. Median age at diagnosis was 3.4 years (IQR, 2.4-5.2). Testing each metabolite for a difference in the mean between healthy and CD children, we (1) could not identify a discriminant analyte or a pattern pointing towards an altered metabolism (Bonferroni corrected P > 0.05 for all). Metabolite concentrations (2) did not differ across the HLA-risk groups. When investigating the age at diagnosis using (3) survival models, we found no evidence for an association between the metabolic profile and the risk of a later CD diagnosis. CONCLUSION: The metabolic profile at 4 months of age was not predictive for the development of CD up to the age of 8 years. Our results suggest that metabolic pathways reflected in serum are affected only later in life and that the HLA-genotype does not influence the serum metabolic profile in young infants before introduction of solid food.

Influence of exclusive enteral nutrition therapy on bone density and geometry in newly diagnosed pediatric Crohn's disease patients.

BACKGROUND AND AIMS: Exclusive enteral nutrition (EEN) induces remission in patients with Crohn's disease (CD). We investigated the short-term impact of EEN on bone quality and muscle mass in children with CD. METHODS: Ten newly diagnosed CD patients (7 male, 10.6-17.7 years of age) were assessed by peripheral quantitative computed tomography (pQCT) at the forearm before starting an 8-weeks treatment with EEN, and after 12 and 52 weeks. No steroids or biologicals were applied. Trabecular and cortical bone mineral density, total bone, and muscle cross-sectional area (CSA) were measured by pQCT and expressed as age- and sex-specific z-scores; size-dependent CSAs were corrected for low height for age. Wilcoxon rank sum test was applied. RESULTS: Remission at week 12 was achieved in 8 patients; 2 still had mild disease. Initially low trabecular density z-scores improved (+0.3; p = 0.006) at week 12; simultaneously, the increased cortical density z-scores normalized (-0.4; p = 0.027). The low z-score for muscle CSA corrected for height (median -2.5, range -3.49 to -0.97) increased within 12 weeks (+1.0; p = 0.002) with no further improvement thereafter. CONCLUSIONS: The results indicate disturbed bone remodeling and severely impaired muscle mass in newly diagnosed CD children. Bone metabolism and muscle mass improved within 3 months after starting EEN with no further normalization thereafter.

Management of coeliac disease patients after the confirmation of diagnosis in Central Europe.

BACKGROUND: Recently published paediatric guidelines for diagnosing coeliac disease do not include recommendations on the follow-up of coeliac disease patients. GOAL: The aim of this study was to assess the management practices and experience of coeliac disease patients with their follow-up appointments in Central Europe. STUDY: Gastroenterologists and coeliac disease patients in five Central European countries were asked to complete the web-based questionnaire focusing on coeliac disease management practices. RESULTS: Answers from 147 gastroenterologists and 2041 coeliac disease patients were available for the analysis. More than half of the gastroenterologists (58.5%) schedule the first follow-up visit within 3 months after the diagnosis. At follow-up, tissue transglutaminase antibodies are checked in almost all patients (95.9%). Approximately two-thirds (60.7%) of gastroenterologists refer all of their patients to the dietitian at diagnosis. Similarly, 42.8% of coeliac disease patients reported that they had not been appointed to a dietitian. Almost one-third of coeliac disease patients (30.8%) reported that they had no follow-up appointments with gastroenterologist at all. CONCLUSIONS: Follow-up of coeliac disease patients is suboptimal in Central Europe. Many patients are not followed regularly. A lot of patients are not referred to a dietitian. The recommendations on the optimal follow-up of coeliac disease patients are needed in order to improve patient care.

Long-term development of bone geometry and muscle in pediatric inflammatory bowel disease.

OBJECTIVES: The muscle-bone unit is crucial for normal bone development. As muscle mass is frequently reduced in pediatric patients with inflammatory bowel disease (pIBD), we investigated the impact of muscles on the bone development over time. METHODS: Bone and muscle parameters were measured repeatedly in 102 pIBD patients (67 boys; 82 Crohn's disease; 30 newly diagnosed) by peripheral quantitative computed tomography (pQCT) at the forearm. The first and last measurements were included in the evaluation. Results were expressed as sex- and age-specific and partly height-corrected Z-scores for a healthy reference population. RESULTS: At baseline, patients showed reduced Z-scores for height (median -0.7; range -3.7 to 1.6), trabecular bone mineral density (TrbBMD; -0.6; 3.0-2.8), and for height-corrected cortical cross-sectional area (CSA(height); -0.4; -3.0 to 2.2), cortical thickness (CrtTh(height); -0.7; -3.0 to 1.2), and MuscleCSA(height) (-1.0; -4.9 to 2.0; all P<0.01). Cortical bone mineral density (CrtBMD) and height-corrected TotalCSA(height) Z-scores were elevated (0.57; -4.55 to 2.8, both P<0.01). Over time, TotalCSA(height) (+0.36; -1.5 to 4.5) further increased, CorticalCSA(height) (+0.21; -2.1 to 3.0) and MuscleCSA(height) (+0.64; -2.0 to 3.9, all P<0.01) improved, whereas CrtBMD decreased toward normalization (-0.36; -5.1 to 3.6, P<0.05). The change in MuscleCSA(height) significantly correlated with the changes in TrbBMD (r=0.42), TotalCSA(height) (r=0.35), CorticalCSA(height) (r=0.38), and CrtTh(height) (r=0.24; all P<0.02). The relations became even stronger after adjustment for several confounders. CONCLUSIONS: Bone metabolism and geometry are altered in pIBD patients expressed by low trabecular mineral density, low cortical thickness, and high cortical mineral density. The increased height-corrected cortical CSA might reflect a compensatory effect. In our cohort, treatment increased height-corrected muscle CSA and its changes were closely associated with bone parameters. Therefore, physical activity to enhance muscle mass and bone health should be promoted in pIBD patients.

Metabolomic Signatures in Pediatric Crohn's Disease Patients with Mild or Quiescent Disease Treated with Partial Enteral Nutrition: A Feasibility Study.

Little is known about the metabolic response of pediatric Crohn's disease (CD) patients to partial enteral nutrition (PEN) therapy and the impact of disease activity and inflammation. We analyzed plasma samples from a nonrandomized controlled intervention study investigating the effect of partial enteral nutrition (PEN) on bone health and growth throughout one year with untargeted metabolomics using high-performance liquid chromatography (HPLC) coupled with high-resolution mass spectrometry (HRMS). Thirty-four paired samples from two time points (baseline and 12 months) were analyzed. Patients (median age: 13.9 years, range: 7-18.9 years, 44% females) were in remission or had mild disease activity. The intervention group received a casein-based formula for 12 months, providing ~25% of estimated daily energy requirements. Sparse partial least squares discriminant analysis (splsda) was applied for group discrimination and identifying sources of variation to identify the impact of PEN. We also investigated the correlation of metabolites with inflammation markers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fecal calprotectin. After 12 months, our results show substantial difference between PEN and non-PEN groups in the metabolome of CD patients in remission or with mild disease activity. Inflammatory markers were associated with individual compounds and chemical classes such as isoprenoids and phospholipids. Identified compounds comprise metabolites produced by human or bacterial metabolism, as well as xenobiotics recognized as flavoring agents and environmental contaminants and their biotransformation products. Further longitudinal studies that also include patients with higher disease activity are warranted to evaluate the suitability of these metabolic biomarkers for predicting disease activity.

Partial enteral nutrition has no benefit on bone health but improves growth in paediatric patients with quiescent or mild Crohn's disease.

BACKGROUND AND AIMS: Exclusive enteral nutrition induces remission, improves bone health and growth in paediatric Crohn's disease (CD) patients, but is highly demanding for patients. We investigated efficacy of partial enteral nutrition (PEN) on bone health, growth and course in CD patients and assessed microbial and metabolic changes induced by PEN. METHODS: We performed a two centre, non-randomized controlled intervention study in quiescent CD patients aged <19 years. Patients in intervention group received a liquid formula providing ~25% of daily energy for one year. At baseline, after 3, 6, 9 and 12 months, we collected data on bone, muscle (peripheral quantitative computertomography), anthropometry, disease activity (weighted paediatric CD activity index), metabolomic profile (liquid chromatography mass spectrometry), and faecal microbiome (16S rRNA gene sequencing). RESULTS: Of 41 CD patients, 22 received the intervention (PEN) (mean age 15.0 ± 1.9 years, 50% male), 19 served as controls (non-PEN) (12.8 ± 3.1 years, 58% male). At baseline, mean bone quality was comparable to reference population with no improvement during the intervention. Relapse rate was low (8/41, PEN 4/22 and non-PEN 4/19, ns). PEN was not associated with microbiota community changes (beta diversity) but significantly reduced species diversity. Metabolome changes with upregulation of phosphatidylcholines in PEN patients are likely related to lipid and fatty acid composition of the formula. PEN significantly improved growth in a subgroup with Tanner stage 1-3. CONCLUSION: In our cohort of paediatric CD patients, PEN did not affect bone health but improved growth in patients with a potential to grow.