Mucosal Atrophy Predicts Poorer Outcomes in Pediatric Ulcerative Colitis-A National Inception Cohort Study.

BACKGROUND: Outcomes in pediatric ulcerative colitis (UC) are heterogeneous and predictors of disease course eagerly sought. Mucosal atrophy (MA) is characterized by histological abnormalities of colonic intestinal glands. OBJECTIVE: To determine the prevalence of MA in a national inception cohort of pediatric UC and its impact on outcomes. METHODS: Irish children < 16 years old with UC are diagnosed at a single referral center. At diagnosis, patients underwent phenotyping by Paris classification and activity assessment by Pediatric Ulcerative Colitis Activity Index. Biopsies from all colonic segments were evaluated for MA. Patients were followed prospectively. The primary outcome was corticosteroid-free remission at 1 year. Secondary outcomes included relapse, treatment escalation, and colectomy by 2 years. RESULTS: Of 251 pediatric patients with UC (mean age 11.8 years, 55% male), 38 (15%) had MA on diagnostic biopsy. Baseline characteristics were similar between groups with/without MA and there was no difference in steroid-free remission or rates of moderate-severe UC at 1 year. Patients with MA had higher use of steroids (29% vs 15%, P = 0.04) and immunomodulators (40% vs 21%, P = 0.04) at 6 months, higher biologic use at 1 year (34% vs 16%, P = 0.03), earlier first relapse (mean ± SD 29.4 ± 26.1 vs 46.7 ± 43.4 weeks after diagnosis, P = 0.02), and higher colectomy rates by 2 years (21% vs 8%, P = 0.01). CONCLUSIONS: Children with MA at diagnosis had higher colectomy rates despite earlier treatment escalation and similar baseline severity scores. We identify MA as a promising new prognostic marker in children with newly diagnosed UC.

Nonsense mutation in the novel PERCC1 gene as a genetic cause of congenital diarrhea and enteropathy.

Congenital diarrheas and enteropathies (CODEs) constitute a heterogeneous group of individually rare disorders manifesting with infantile-onset chronic diarrhea. Genomic deletions in chromosome 16, encompassing a sequence termed the 'intestine-critical region (ICR)', were recently identified as the cause of an autosomal recessive congenital enteropathy. The regulatory sequence within the ICR is flanked by an unannotated open reading frame termed PERCC1, which plays a role in enteroendocrine cell (EEC) function. We investigated two unrelated children with idiopathic congenital diarrhea requiring home parenteral nutrition attending the Irish Intestinal Failure Program. Currently 12 and 19-years old, these Irish male patients presented with watery diarrhea and hypernatremic dehydration in infancy. Probands were phenotyped by comprehensive clinical investigations, including endoscopic biopsies and serum gastrin level measurements. Following negative exome sequencing, PCR and Sanger sequencing of the entire coding region and intron boundaries of PERCC1 were performed for each proband and their parents. In both patients, serum gastrin levels were low and failed to increase following a meal challenge. While no deletions involving the ICR were detected, targeted sequencing of the PERCC1 gene revealed a shared homozygous c.390C > G stop gain variant. We report clinical and molecular findings in two unrelated patients harboring a shared homozygous variant in PERCC1, comprising the first description of a point mutation in this gene in association with CODE. That both parenteral nutrition dependent children with unexplained diarrhea at our institution harbored a PERCC1 mutation underscores the importance of its inclusion in exome sequencing interpretation.

NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation.

Dysregulated redox signaling and oxidative injury are associated with inflammatory processes and fibrosis. H2O2 generation by NOX4 has been suggested as a key driver in the development of fibrosis and a small molecule drug is under evaluation in clinical trials for idiopathic pulmonary fibrosis and primary biliary cholangitis. Fibrosis is a common complication in Crohn's disease (CD) leading to stricture formation in 35-40% of patients, who require surgical interventions in the absence of therapeutic options. Here we assess NOX4 expression in CD patients with inflammatory or stricturing disease and examine whether loss of NOX4 is beneficial in acute and fibrotic intestinal disease. NOX4 was upregulated in inflamed mucosal tissue of CD and ulcerative colitis (UC) patients, in CD ileal strictures, and in mice with intestinal inflammation. Nox4 deficiency in mice promoted pathogen colonization and exacerbated tissue injury in acute bacterial and chemical colitis. In contrast, in two chronic injury models aberrant tissue remodeling and fibrosis-related gene expression did not differ substantially between Nox4-/- mice and wildtype mice, suggesting that Nox4 is dispensable in TGF-ß1-driven intestinal fibrogenesis. While animal models do not recapitulate all the hallmarks of CD fibrosis, the tissue-protective role of Nox4 warrants a cautious approach to pharmacological inhibitors.

Correction to: NADPH Oxidases in Inflammatory Bowel Disease.

The title of Chapter 38 was published with a typo error. It should read "NADPH Oxidases in Inflammatory Bowel Disease", whereas the title was mistakenly printed as "NAPDH Oxidases in Inflammatory Bowel Disease" and the book has been updated for this error.

NAPDH Oxidases in Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD), categorized as ulcerative colitis (UC), Crohn's disease (CD), or IBD-undetermined (IBDU), are increasing in incidence. IBD is understood to result from environmental factors interacting with a pre-existing genetic susceptibility. Approximately 1% of all patients with inflammatory bowel disease (IBD) are diagnosed before the age of 6 years, designated as very-early-onset IBD (VEOIBD). This cohort of patients is distinguished from other age groups by differences in disease phenotype and by a higher burden of genetic mutations. Recent studies have linked mutations in NADPH oxidase function to VEOIBD and even pediatric IBD. Loss-of-function NOX2 variants expressed in phagocytes and NOX1/DUOX2 variants expressed in intestinal epithelial cells have been associated with VEOIBD and pediatric and adult IBD in patients. Cell and animal studies suggest a protective role for these reactive oxygen species (ROS)-producing enzymes in intestinal homeostasis-a paradigm that challenges the conventional concept that only increased ROS result in cell and tissue damage. Examining the role of NADPH oxidases in VEOIBD may improve our understanding of the pathophysiology of this disease and will uncover new therapeutic possibilities.

Crohn's Strictures-Moving Away from the Knife.

Crohn's disease (CD) is a lifelong inflammatory bowel disease with a rapidly rising incidence in the pediatric population. A common complication of CD is the development of fibrotic strictures, which may be present at initial diagnosis or develop many years later. Clinical presentation depends on stricture location and degree of obstruction, and strictures frequently contain a mixture of inflammatory and fibrotic tissue. Histological examination of Crohn's strictures shows thickening of the muscular layers and the submucosa, where increased collagen deposition by activated myofibroblasts is concentrated around islands of smooth muscle cells and at the superficial margin of the muscularis propria. No antifibrotic therapies for Crohn's strictures exist. Profibrotic transforming growth factor-ß (TGFß)/bone morphogenetic protein signaling stimulates myofibroblast differentiation and extracellular matrix deposition. Understanding and targeting TGFß1 downstream signaling is the main focus of current research, raising the possibility of specific antifibrotic therapy in CD becoming available in the future.

A randomised trial of placing preterm infants on their back or left side after birth.

BACKGROUND: Basic life support guidelines recommend placing spontaneously breathing children and adults on their side. Though the majority of preterm newborns breathe spontaneously, they are routinely placed on their back after birth. We hypothesised that they would breathe more effectively when placed on their side. OBJECTIVE: To determine whether preterm newborns placed on their left side at birth, compared with those placed on their back, have higher preductal oxygen saturation (SpO2) at 5 min of life. DESIGN/METHODS: We randomised infants <32 weeks to be placed on their back or on their left side immediately after birth. Respiratory support was given with a T-piece and face mask with initial fraction of inspired oxygen (FiO2) of 0.3. The FiO2 was increased if SpO2 was <70% at 5 min. RESULTS: We enrolled 87 infants, 41 randomised to back and 46 to left side. The groups were well matched for demographic variables. Fourteen (6 back and 8 left side) infants did not receive respiratory support in the first 5 min. The mean (SD) SpO2 was not different between the groups (back 72 (23) % versus left side 71 (24) %, p=0.956). We observed no adverse effects of placing infants on their side and found no differences in secondary outcomes between the groups. CONCLUSIONS: Preterm infants on their left side did not have higher SpO2 at 5 min of life. Placing preterm infants on their side at birth is feasible and appears to be a reasonable alternative to placing them on their back. TRIAL REGISTRATION NUMBER: ISRCTN74486341.

Ulcerative colitis: management in adults, children and young people (NICE Clinical Guideline CG166).

The National Institute for Health and Care Excellence (NICE) published a clinical guideline in 2013 entitled 'Ulcerative colitis: Management in adults, children and young people (NICE Clinical Guideline CG166)'. This guideline review discusses the evidence base, compares the guideline with current practice and published guidelines, and summarises the key points relevant to pediatricians who manage children with UC.

Highly accurate prediction of food challenge outcome using routinely available clinical data.

BACKGROUND: Serum specific IgE or skin prick tests are less useful at levels below accepted decision points. OBJECTIVES: We sought to develop and validate a model to predict food challenge outcome by using routinely collected data in a diverse sample of children considered suitable for food challenge. METHODS: The proto-algorithm was generated by using a limited data set from 1 service (phase 1). We retrospectively applied, evaluated, and modified the initial model by using an extended data set in another center (phase 2). Finally, we prospectively validated the model in a blind study in a further group of children undergoing food challenge for peanut, milk, or egg in the second center (phase 3). Allergen-specific models were developed for peanut, egg, and milk. RESULTS: Phase 1 (N = 429) identified 5 clinical factors associated with diagnosis of food allergy by food challenge. In phase 2 (N = 289), we examined the predictive ability of 6 clinical factors: skin prick test, serum specific IgE, total IgE minus serum specific IgE, symptoms, sex, and age. In phase 3 (N = 70), 97% of cases were accurately predicted as positive and 94% as negative. Our model showed an advantage in clinical prediction compared with serum specific IgE only, skin prick test only, and serum specific IgE and skin prick test (92% accuracy vs 57%, and 81%, respectively). CONCLUSION: Our findings have implications for the improved delivery of food allergy-related health care, enhanced food allergy-related quality of life, and economized use of health service resources by decreasing the number of food challenges performed.