Epstein-Barr Virus Prevalence at Diagnosis and Seroconversion during Follow-Up in Pediatric Inflammatory Bowel Disease.

Primary Epstein-Barr virus infection in pediatric patients with inflammatory bowel disease during immunomodulation with thiopurines has been associated with increased risk for malignancies or hemophagocytic lymphohistiocytosis. We determined Epstein-Barr virus (EBV) seroprevalence at inflammatory bowel disease (IBD) diagnosis and seroconversion during follow-up in a large single center cohort of children with IBD. EBV serology results and patient characteristics were retrospectively retrieved from the hospital documentation system. EBV seronegative patients at IBD diagnosis were prospectively retested. We report on IBD patients with symptomatic active EBV infection and a complicated disease course, and those diagnosed with malignancy with respect to EBV status and drug exposure. Of 402 patients, 194 (48%) had available EBV serology results at time of IBD diagnosis at a median of 12 years (IQR 9-14 years). Thereof, 102 (53%) were EBV-positive. Of 92 EBV-negative patients, 66 were retested and 17% showed a seroconversion at a mean follow-up time of 4.3 years (SD 3 years). Three children treated with azathioprine experienced acute clinically relevant EBV infection 2, 2.5, and 4 years after IBD diagnosis, two developed signs of hemophagocytic lymphohistiocytosis. Three cases of malignancy occurred in the cohort, though none seemed to be triggered by EBV. In conclusion, almost 50% of pediatric IBD patients were EBV-naïve following diagnosis and may be at increased risk to develop severe EBV infection during immunosuppressive therapy, potentially associated with complications such as hemophagocytic lymphohistiocytosis or malignancy.

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.

Fecal Markers of Inflammation and Disease Activity in Pediatric Crohn Disease: Results from the ImageKids Study.

BACKGROUND: Noninvasive and accurate methods to monitor inflammatory bowel disease are required. As a planned ancillary study of the prospective ImageKids cohort, we aimed to assess the performance of fecal calprotectin (FC) with comparison to 3 fecal inflammatory markers; S100A12 (FA12), tumor pyruvate kinase isoenzyme type M2 (FM2PK) and fecal osteoprotegerin (FOPG) as indicators of a number of disease characteristics. METHODS: The ImageKids study was a multicenter study designed to develop 2 magnetic resonance enterography-based measures for children with Crohn disease (6-18 years old). All patients underwent magnetic resonance enterography, a complete ileocolonoscopic evaluation and provided a fecal sample. Fecal samples were assay for FC, FA12, FM2PK, and FOPG by ELISA. RESULTS: One-hundred fifty-six children provided 190 fecal samples. Median (interquartile range) for fecal makers were FC, 602 (181-1185) µg/g; FA12, 21 (3-109) µg/g; FM2PK, 16 (2-20) U/mL; and FOPG, 125 (125-312) µg/g. All markers correlated with simple endoscopic severity index for Crohn disease and with other constructs of disease activity, but FC had the highest overall correlations. FA12, however, predicted mucosal healing with significantly higher specificity (87% vs 70%, P = 0.004) and equivalent sensitivity (91% vs 90%) compared to FC. CONCLUSION: This study has confirmed that FC is useful, and overall best, marker to monitor mucosal inflammation in inflammatory bowel disease. FA12, however, appears to be a more suitable maker for prediction of mucosal healing in children.

Magnetic Resonance Enterography Cannot Replace Upper Endoscopy in Pediatric Crohn Disease: An Imagekids Sub-study.

OBJECTIVES: Although magnetic resonance enterography (MRE) can accurately reflect ileal inflammation in pediatric Crohn disease (CD), there are no pediatric data on the accuracy of MRE to detect upper gastrointestinal tract (UGI) lesions. We aimed to compare MRE and esophagogastroduodenoscopy (EGD) in detecting the spectrum and severity of UGI disease in children. METHODS: This is an ancillary study of the prospective multi-center ImageKids study focusing on pediatric MRE. EGD was performed within 2 weeks of MRE (at disease onset or thereafter) and explicitly scored by SES-CD modified for the UGI and physician global assessment. Local and central radiologists scored the UGI region of the MRE blinded to the EGD. Accuracy of MRE compared with EGD was examined using correlational coefficients (r) and area under receiver operating characteristic curves (AUC). RESULTS: One hundred and eighty-eight patients were reviewed (mean age 14 ±â€Š1 years, 103 [55%] boys); 66 of 188 (35%) children had macroscopic ulcerations on EGD (esophagus, 13 [7%]; stomach, 34 [18%]; duodenum, 45 [24%]). Most children had aphthous ulcers, but 10 (5%) had larger ulcers (stomach, 2 [1%]; duodenum, 8 [4%]). There was no agreement between local and central radiologists on the presence or absence of UGI inflammation on MRE (Kappa = -0.02, P = 0.71). EGD findings were not accurately detected by MRE, read locally or centrally (r = -0.03 to 0.11, P = 0.18-0.88; AUC = 0.47-0.55, P = 0.53-1.00).No fistulae or narrowings were identified on either EGD or MRE. CONCLUSIONS: MRE cannot reliably assess the UGI in pediatric CD and cannot replace EGD for this purpose.

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.