Characterization and Short-Term Outcome of Potential Celiac Disease in Children.

Background and Objectives: Potential Celiac Disease (PCD) is defined by positive celiac serology without villous atrophy. We aimed to describe the short-term outcome of pediatric PCD while consuming a gluten-containing diet (GCD). Materials and Methods: Retrospective analysis of pediatric PCD patients continuing GCD, between December 2018-January 2022. Baseline demographics, celiac serology and duodenal biopsy results were reviewed. Follow-up data included repeated serology and biopsy results when performed. Minimum follow-up was 12 months unless celiac disease (CeD) was diagnosed earlier. Results: PCD was diagnosed in 90 children (71% females) with a mean age of 7.2 (range 1.8-16.5) years. Baseline anti-tissue transglutaminase (TTG) levels were above 10 times the upper limit of normal (ULN) in 17/90 (18.9%), 3-10 × ULN in 56/90 (62.2%) and 1-3 × ULN in 17/90 (18.9%). During follow-up, the mean time was 17.6 (range 5-35) months, TTG normalized in 34/90 (37.8%), was stable in 48/90 (53.3%), and increased or remained >10 × ULN in 8/90 (8.9%). In 20/90 (22.2%) patients, a repeat endoscopy was performed, leading to CeD diagnosis in 12/20 (60%). Thus, at the end of follow-up, CeD was diagnosed in 12/90 (13.3%). In patients with TTG >10 × ULN at diagnosis, TTG normalized in 5/17, decreased to 3-10 × ULN in 8/17, and remained above 10 × ULN in 4/17. Conclusions: During the short-term follow-up of pediatric PCD patients, less than 15% progressed to CeD. A third had normalized TTG levels, including children with TTG >10 × ULN, indicating the need for periodic serological and histological follow-up among PCD patients.

Mucus sialylation determines intestinal host-commensal homeostasis.

Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.

Real-life Performance of Multiplex Celiac Antibody Test in the Diagnosis of Pediatric Celiac Disease.

OBJECTIVE: Tissue-transglutaminase antibodies (TGA) may be used to diagnose celiac disease (CD) without biopsy in selected cases. We aimed to investigate real-life performance of a CD serology automated analyzer (Bioplex2200), and to explore the correlation between TGA levels and intestinal biopsies in children. METHODS: A retrospective review was performed in 2 pediatric gastroenterological centers, between November 1, 2018 and April 1, 2020 and included patients with both TGA serology testing and duodenal biopsies. Retrieved data included patients' demographics, medical background, TGA levels, and biopsy results. RESULTS: Overall, 538 children were evaluated, 256 with positive TGA (68.4% girls, median age 6.4 years), and 282 with negative TGA (53.9% girls, median age 13.4 years). Among patients with positive TGA, intestinal biopsies confirmed CD in 219 (85.5%). Overall, positive serology with normal histology was found in 14.5% of the cohort, with 52%; 21.6%; 21.1%; and 4.2% in TGA ranges of 1 to 3 times upper limit of normal (ULN); 3 to 5 ULN; 5 to 10 ULN; and above 10 times ULN, respectively, P < 0.001. Area under the receiver-operating characteristic curve (AUC) was 0.963 (95% CI 0.947-0.980). Among patients with positive TGA, 216 (84.4%) had positive anti-endomysial antibodies. In this sub-group, the overall diagnostic performance was inferior, with AUC of 0.737 (95% CI 0.834-0.839). CONCLUSIONS: The Multiplex TGA assay had a very high diagnostic accuracy in real-life. Among patients with positive TGA, adding EMA did not improve the diagnostic performance of the test. False-positive rates differed between different ranges of TGA and were low with TGA above 10 times ULN.

Long-Term Follow-up and Predictors of Complicated Disease Behavior in Pediatric Crohn's Disease Patients.

OBJECTIVE: Identifying predictors of inflammatory bowel disease (IBD) outcome in order to optimize individual patient management in has become an important goal. We aimed to describe the long-term outcome of pediatric Crohn disease (CD) patients and identify risk factors for complicated behavior. METHODS: Pediatric CD patients diagnosed between 1998 and 2014, with long-term follow-up were included. Baseline data; age, gender, weight/height/BMI percentiles, and family history of IBD. Disease characteristics (Paris classification), laboratory testing, imaging and treatment were documented. Outcome data; evidence of stricturing or penetrating disease, hospitalizations, surgical intervention, malignancies, and mortality. RESULTS: Of 93 patients included, mean age at diagnosis 13.5 (±3.2), 51 (55%) male, median follow-up 10.3 years (±4 SD(. Disease location at diagnosis: 29 (31.2%) distal ileum, 17 (18.3%) colonic, 40 (43.0%) ileo-colonic. Seven (7.5%) had upper gastrointestinal and 36 (38.7%) perianal involvement. Behavior at diagnosis, 68 (73.1%) inflammatory (B1), and 25 (26.9%) complicated [(B2 (stricturing) and/or B3 (penetrating)]. Twenty (23.2%) of B1 evolved to B2 and/or B3, thus by the end of follow-up 45 (48.4%) had complicated behavior. Sixty-seven (72%) were hospitalized, 20 (21.5%) underwent surgery, two developed malignancy with no mortalities. In a logistic regression model, growth delay (hazard ratio [HR], 5.02 [1.10-22.85], P = 0.037) and low albumin levels (HR, 3.97 [1.32-11.97], P = 0.014) at diagnosis were predictors of complicated disease in adulthood. CONCLUSIONS: Over a quarter of pediatric Crohn disease patients present with complicated behavior. During follow-up another quarter progress to complicated disease behavior. Delayed growth and low albumin at diagnosis predict progression.

Adherence to gluten-free diet and follow-up of pediatric celiac disease patients, during childhood and after transition to adult care.

Long-term data on pediatric celiac disease (CD) patients after transition to adult care is scarce. We aimed to evaluate patients' adherence to a gluten-free diet (GFD), the normalization of celiac serology and the frequency of follow-up before age 18, and to study changes in adherence and follow-up frequency after transition to adult care. Presenting symptoms, serology and biopsy results, patients' reported GFD adherence, frequency of follow-up visits, and complications before and after 18 years were collected for CD patients diagnosed between 1998 and 2017. Of 441 CD patients diagnosed and followed in childhood, a quarter (108/441) were over 18 y (years) at data collection. Median age at diagnosis 7.1 y (9 months-18 y), at data collection 23 y (18-38 y), disease duration 11.3 y (2-36 y). Below the age of 18 y, most patients 386/436 (88.5%) reported adherence to GFD, and most 372/425 (85.7%) normalized serology. Of the 441 patients, only 3 failed to attend any follow-up visit, and 338/441 (76.6%) attended yearly visits. Over the age 18 y, serology testing was done in 78/108 (72.2%), every 1-3 y in 46/78 (59%). Serology normalized in 61/78 (78.2%). Most adult patients 77/108 (71.5%) never attended a gastroenterology clinic. CD-related complications were rare. Younger age at diagnosis, regular follow-up visits in childhood, resolution of symptoms, and normalization of serology before age 18 were identified as predictors of negative serology after the age of 18 y.Conclusions: Children who have regular follow-up and normalize serology before age 18 years are likely to maintain a GFD and have negative serology as adults. What is Known: • The rate of adherence to gluten-free diet (GFD) is higher among children compared to adults. • Data on long-term follow-up after transition to adult care is scarce. What is New: • Patients diagnosed with CD at a younger age (<12 y), who have yearly follow-up visits, resolution of symptoms, and negative serology in childhood are very likely to maintain GFD and have negative serology as adults. • Even though most patients do not attend GI clinics after transition to adulthood, most adhere to GFD, and complications are rare.

Reassessing vitamin D supplementation in preterm infants: a prospective study and review of the literature.

Objectives Recommendations for vitamin D (VitD) intake and target serum levels of 25(OH)D in preterm infants are diverse. We hypothesized that preterm infants with low birth weight (BW) have low dietary intake of VitD and therefore should be supplemented with higher amounts of VitD. Methods Infants with BW < 2 kg were supplemented with 600 units of VitD a day during the first 2-6 weeks of life, whereas infants with BW>2 kg continued with the routine supplementation of 400 units of VitD daily. Serum levels of 25(OH)D, calcium, phosphorous, alkaline phosphatase (AP) and parathyroid hormone (PTH) were assessed 24 h after birth and before discharge. The total daily intake of vitD was calculated in each infant. Results Sixty-two infants were enrolled, 49 with BW < 2 kg. After birth, only 24% had sufficient levels of 25(OH)D, whereas before discharge 45 of 54 infants (83%) available for analysis reached sufficient levels of 25(OH)D. All 54 infants demonstrated significant elevation in serum levels of calcium, phosphorous, AP and significant reduction in PTH levels. The total daily intake of VitD was lower than recommended (800-1000 IU/d) in 16 of 45 infants with BW < 2 kg (36%) and in all nine infants with BW>2 kg. Nevertheless, only 2 of 25 infants with insufficient intake of VitD demonstrated insufficient levels of serum 25(OH)D. No case of vitamin D excess was recorded. Conclusions Increased supplementation of VitD (600 IU/d) for premature newborns with BW < 2 kg is effective in increasing both total daily intake of VitD and serum levels of 25(OH)D.

Lack of association between Helicobacter pylori infection and childhood overweight/obesity.

BACKGROUND: The reduction in the prevalence of Helicobacter pylori (H. pylori) infection in developed countries coincides with the increasing incidence of obesity and might be a contributing factor to the obesity epidemic. We aimed to evaluate the association between H. pylori infection and childhood overweight/ obesity in Israeli children. MATERIAL AND METHODS: Patients diagnosed with H. pylori infection by endoscopy, histology, and a positive culture, between January 2013 and August 2018, were identified and compared with H. pylori-negative children, of the same age and gender, undergoing endoscopy for the same indications during the same time period. Data collected included the following: age, gender, height, weight, BMI, BMI percentile, and the indication for endoscopy. Patients with missing anthropometric data or having a disease affecting growth were excluded. RESULTS: We included 146 H. pylori-positive children and 146 age- and gender-matched H. pylori-negative patients. 63.7% (186/292) were female, mean age 13.1 ± 3.7. Overweight (BMI between the 85th-95th percentile) and obesity (BMI > 95th percentile) were present in 56/292 (19.2%). Among the H. pylori-positive children, 11.6% were overweight, 7.5% obese, among the H. pylori-negative children, 10.3% were overweight, 8.9% obese, demonstrating no differences between the groups. The main indication for endoscopy was abdominal/ epigastric pain in 79.8% (233/292). The percent of children with a BMI ≥ 85% did not differ by gender age or the indication for endoscopy. CONCLUSIONS: No association between H. pylori infection and childhood overweight/ obesity was demonstrated. This is in contrasts with previous pediatric studies demonstrating an inverse correlation.

Outcomes Following Pouch Formation in Paediatric Ulcerative Colitis: A Study From the Porto Group of ESPGHAN.

INTRODUCTION: Contemporary pediatric data on pouch outcomes are sparse, especially in the era of laparoscopic surgeries. We aimed to assess outcomes and predictors in children with ulcerative colitis/inflammatory bowel disease (IBD)-unclassified who underwent colectomy and ileal pouch-anal anastomosis. METHODS: This was a multicenter retrospective cohort study from 17 IBD centers affiliated with the pediatric IBD Porto group of ESPGHAN. An electronic REDcap system was used to collate baseline characteristics, demographic, clinical, management and surgical data, short- and long-term outcomes, and to identify potential predictors of pouch outcome. RESULTS: Of the 129 patients included, 86 (67%) developed pouchitis during follow-up of median 40 months (interquartile range 26-72), of whom 33 (26%) with chronic pouchitis. Patients operated on by surgeons performing <10 pouch surgeries/year had a higher rate of chronic pouchitis (11/27 [41%] vs 8/54 [15%], P = 0.013) on both univariable and multivariable analyses and also associated with time to pouchitis (P = 0.018) and chronic pouchitis (P = 0.020). At last follow-up, overall pouch performance was rated good/excellent in 86 (74%) patients. Time from colectomy to pouch formation was not associated with pouch outcomes. Despite higher rate of nonsevere surgical complications among children undergoing colectomy at <10 years of age (7/16 [44%] vs 10/92 [11%], P = 0.003), functional outcome and pouchitis rate did not differ. CONCLUSIONS: Pouchitis rate in children with ulcerative colitis/IBD unclassified is high. Surgeon experience is the major modifiable risk factor for pouch outcome. Our analyses suggest that pouch surgery can also be performed successfully in young children.

The Effect of Adalimumab Treatment on Linear Growth in Children With Crohn Disease: A Post-hoc Analysis of the PAILOT Randomized Control Trial.

OBJECTIVES: Growth impairment is common in children with Crohn disease (CD). We aimed to assess the effect of adalimumab (ADL) treatment on linear growth in children with CD in a post-hoc analysis of the Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment randomized controlled trial. METHODS: Children 6 to 17 years who responded to ADL induction were assessed consecutively for anthropometric parameters. Associations of these parameters with disease characteristics and disease activity were analyzed. RESULTS: Overall, 66 patients completed 72 weeks of follow-up (25% girls, mean age of 15.6 ±â€Š2.5 years). Median (interquartile range [IQR]) height z score improved from -0.6 (-1.6-0.15) at baseline to -0.33 (-1.3-0.5) at week 72 (P = 0.005) with lesser improvement in patients with perianal disease. Similar effect was noted in children with growth potential (boys younger than 16 years, girls younger than 14 years). Median (IQR) height velocity standard deviation was -0.32 (-1.5-0.8) at week 26, and +0.11 (-1.1-1.3) at week 72. Median weight z score increased from -0.54 (-1.2-0.15) to -0.1 (-0.9-0.6), P < 0.001 and body mass index from -0.4 (-1.0-0.5) to 0.0 (-0.8-0.9), P = 0.005. Pediatric CD activity index and erythrocyte sedimentation rate at week 4 correlated negatively with height z score changes (P = 0.043 and P = 0.048, respectively), whereas sustained clinical and biologic remission (week 4-72) were positively associated with changes in height z scores. Significant improvement in linear growth was predicted by lower pediatric CD activity index and erythrocyte sedimentation rate at the end of induction and sustained clinical remission (P = 0.05) and sustained normal C-reactive protein (P = 0.001) at all visits. CONCLUSION: In children with moderate-to-severe CD, ADL treatment had a significant effect on linear growth, with normalization of weight and body mass index (clinicaltrials.gov no: NCT02256462).

Combination Therapy of Adalimumab With an Immunomodulator Is Not More Effective Than Adalimumab Monotherapy in Children With Crohn's Disease: A Post Hoc Analysis of the PAILOT Randomized Controlled Trial.

BACKGROUND: The PAILOT trial was a randomized controlled trial aimed to evaluate proactive vs reactive therapeutic drug monitoring in children with Crohn's disease (CD) treated with adalimumab. Our aim in this post hoc analysis of the PAILOT trial was to assess the efficacy and safety of adalimumab combination treatment in comparison with monotherapy at week 72 after adalimumab induction. METHODS: Participants were children 6-17 years old, biologic naïve, with moderate to severe CD, who responded to adalimumab induction at week 4. Patients receiving immunomodulators at baseline maintained a stable dose until week 24; patients could then discontinue immunomodulators. At each visit, patients were assessed for disease index, serum biomarkers, fecal calprotectin, adalimumab trough concentration, and anti-adalimumab antibodies. RESULTS: Out of the 78 patients (29% female; mean age, 14.3 ± 2.6 years), 34 patients (44%) received combination therapy. During the study period, there was no significant difference in the rates of sustained corticosteroid-free clinical remission (25/34, 73%, vs 28/44, 63%; P = 0.35) or sustained composite outcome of clinical remission, C-reactive protein ≤0.5 mg/dL, and calprotectin ≤150 µg/g (10/34, 29%, vs 14/44, 32%; P = 0.77) between the combination group and the monotherapy group, respectively. Clinical and biological outcomes did not differ between the proactive and reactive subgroups within the combination and monotherapy groups. Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but was numerically higher in the monotherapy group. CONCLUSIONS: Combination therapy of adalimumab and an immunomodulator was not more effective than adalimumab monotherapy in children with CD (ClinicalTrials.gov No. NCT02256462).

Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring.

BACKGROUND & AIMS: Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS: We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 µg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS: The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 µg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS: In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.